Research Projects

Abstract

This study aims to advance the cornea-on-chip (CoC), a microfluidic device designed as a microscopy slide, featuring eight corneal constructs to mimic human corneal barriers and physiology. The objective is to validate this prototype via a comprehensive approach as an in vitro model with pre-clinical value of the human cornea, focusing on drug permeability and corneal toxicity testing. By collaborating with Ghent University's Centre for Microsystems Technology, we combine our respective expertise's in corneal tissue engineering and microfluidics with my background in GMP manufacturing to assess the CoC's performance. The CoC platform's efficacy as a drug absorption model is confirmed by assessing corneal permeation and small molecule permeability. Anticipating potential limitations in mimicking the physiology of the cornea in vivo, we will explore biocompatible materials to improve cell behavior and drug permeation, laying the foundation for the model's second and improved version. Furthermore, through multi-omics analysis, I will investigate the interactions between cells and biomaterials to gain valuable insights. Finally, as a proof of concept regarding the application of the model, the cornea-on-chip is used to identify strategies to bypass the corneal barrier via the use of penetration enhancers, to boost drug delivery effectiveness.

Researcher(s)

• Promoter: Koppen Carina
• Co-promoter: Van den Bogerd Bert
• Fellow: De Vos Evelyne

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Hearing loss is the most common sensory deficit and has been recognized by the WHO as a priority disease for research into therapeutic interventions. Deafness Autosomal Dominant 9 (DFNA9) is one of the best-studied forms of dominantly-inherited, adult-onset hearing loss and is characterized by progressive sensorineural hearing loss (SNHL). It is caused by mutations in the COCH gene, which encodes for the protein cochlin. In this project, the applicant presents the development and pre-clinical testing of an optimized delivery method for RNA therapeutics for hearing loss. The applicant will use DFNA9 and the antisense oligonucleotides (ASOs) she validated in vitro, as a case study for this novel treatment paradigm. More specifically, the applicant will go beyond the current state of the art by benchmarking the clinically relevant/feasible intratympanic delivery method and generating a purpose-built hydrogel for ASO treatment. Furthermore, cell-specific uptake of different gapmer ASO chemistries in the inner ear will be studied to achieve targeted delivery. Finally, the applicant will generate data on the pharmacokinetics, safety and efficacy of (gapmer) ASOs in the mammalian inner ear of our genetically engineered humanized DFNA9 mouse model. As such, this project will pave the way for clinical applications of ASOs and other types of gene therapy to target the cochlea for the future treatment of DFNA9 and other inner ear disorders.

Researcher(s)

• Promoter: Van Rompaey Vincent
• Co-promoter: Verdoodt Dorien
• Fellow: Aben Fien

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Hearing loss is a worldwide public health problem that currently affects over 1.5 billion people and around 65% of adults above the age of 60. An accelerated cognitive decline is observed in adults with peripheral hearing loss compared to their normal hearing peers. This indicates an increased risk for the development of dementia in adults with hearing loss, however, the underlying relationship between cognitive functioning and hearing loss remains clear. Previous studies indicated a significant improvement in cognitive functioning after cochlear implantation. The identification of an objective biomarker to identify cognitive functioning in Cochlear implant (CI) users will help unravel the effect of cochlear implantation on cognitive functioning and can provide insight into the underlying neurophysiological processes. The applicant will investigate Evoked response potentials elicited with an auditory and visual oddball paradigm to identify an objective marker for cognitive functioning. Moreover, the applicant will investigate Error monitoring as a potential indicator for cognitive functioning. The overall aim of this study is to identify an objective marker for cognitive functioning independent of hearing levels, that can be used in CI users but also in other patient populations.

Researcher(s)

• Promoter: Van Rompaey Vincent
• Co-promoter: Dhar Monica
• Fellow: Vandenbroeke Tinne

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Obstructive sleep apnea (OSA) is a highly prevalent respiratory sleep disorder. As it is associated with multiple comorbidities including cardio- and cerebrovascular burden, appropriate treatment is crucial. To achieve optimal treatment, both efficacy and adherence should be optimized. Endotyping OSA patients has shown promise for treatment optimization, yet gold-standard assessment is impossible in clinical practice. The site, pattern and degree of collapse is a key factor driving OSA treatment outcome. In current clinical practice, drug-induced sleep endoscopy (DISE) is used to visualize the upper airway during sedation. However, this technique does not allow site of collapse assessment during longer periods and different sleep stages. Recently, I developed a non-invasive means to assess probability of site of collapse using clinical polysomnography that could overcome this issue. Yet, the underlying mechanisms remain unknown. Furthermore, associations with and relative importance of this parameter compared to other non-invasive endotypes remain unclear. Therefore, I aim to 1) assess the underlying mechanistic effects underlying non-invasive site of collapse detection throughout the night to augment the novel method, 2) predict OSA treatment outcome using this method, and 3) develop a holistic model combining anatomical and non-anatomical non-invasive endotypes. As such, I aim to attain precision OSA medicine using endotype-driven instead of guideline-based treatment.

Researcher(s)

• Promoter: Vanderveken Olivier
• Co-promoter: Verbraecken Johan
• Fellow: Op de Beeck Sara

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

During the first years of life the eye grows tremendously, while simultaneously reducing the mean ocular refraction by carefully adjusting the growth speed of the eye globe, cornea, and crystalline lens. This process is called emmetropization and takes place during the first 2–3 years of life. Next, homeostasis occurs, during which eye growth continues while maintain the near-emmetropic refractive error through a combination of scaled growth and active feedback mechanisms. Failure of homeostasis will lead to excessive axial growth and myopia, which causes the retinal image to be out of focus. Animal experiments demonstrated that eye growth involves a delicate interaction between optical and sensory components to provide retinal image clarity throughout life. So, emmetropization is the active, visually guided mechanism whereby the axial length and the combined optical powers of the cornea and lens precisely match with each other to eliminate neonatal refractive errors. Many reports on ocular growth have been published, these are often for a limited age range. Our group recently published a complete overview of normal ocular growth before birth until 18 years of age. Similarly, there are descriptive models for eye growth in the literature, but a quantitative model for the mechanisms of eye growth is currently lacking. This project aims to model the changes of the ocular components involved in visually guided eye growth using differential equations, consisting of two exponential terms representing the scaled growth before birth and the growth with active feedback after birth. Besides, we work on estimating the influence of variations in optical parameters on variations in refractive error using the error propagation method. Moreover, we explore how the parameters of bi-exponential functions can be adjusted to simulate various known refractive development courses described in the literature, such as instant emmetropization, persistent hypermetropia, myopia, and so on. Additionally, it is known from the literature that myopia development is affected by both retinal defocus and the spectral composition of the ambient light. Both factors are known to affect contrast sensitivity function (CSF). It is becoming increasingly clear that CSF may play a large role in refractive development. We measure the CSF of both emmetropes and myopes to investigate the combined effect of defocus and color band on the CSF. Finally, we aim to modulate the exponential function of eye growth (ODE model) and look for the retina response function by considering some important factors such as the CSF of the human eye, the luminance, and the surrounding illumination. Objectives: 1. Propose an active model of normal and abnormal refractive development. 2. Estimate the influence of variations in biometric parameters on variations in refractive error. 3. Propose bi-exponential description for different forms of refractive development. 4. Measure the CSF within the red, green, and blue color bands across different levels of defocus. 5. Develop a modulated ODE model by considering retina function.

Researcher(s)

• Promoter: Rozema Jos
• Fellow: Farzanfar Arezoo

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Ophthalmic research has made significant progress, evolving from basic ocular refractive models to the sophisticated SyntEyes model. The latter model provides synthetic biometric datasets that reflect real eye statistics for improved optical calculations without additional measurements. However, to date its focus remained limited to optical characteristics, leaving out ocular biomechanics. To address this gap, the SyntEyes OBM (Synthetic Opto-Biomechanical Eye Model) is proposed as a comprehensive platform that integrates both optical and biomechanical properties of the eye to perform detailed analyses under different conditions. This advancement involved the development of a 3D geometric eye model including the cornea, limbus, sclera, lens, iris, ciliary body, and zonular fibres. The model uses Zernike coefficients to define the anterior and posterior surfaces of the cornea, extending their diameters to allow for realistic dimensions. The lens shape was derived from SyntEyes data using aspheric surfaces for accuracy. The sclera was modelled as a spherical shell of constant thickness connecting the corneal limbus to the retinal fovea, while the ciliary body and zonular fibres were customised based on previous research to ensure individual representation. The SyntEyes OBM model offers adaptability to multiple biometric variations, enhancing the original SyntEyes by incorporating biomechanical insights and allowing simultaneous and accurate evaluation of the optical and biomechanical aspects of the eye. This model will significantly enhance optical and clinical simulations, providing a more thorough and accurate tool for ophthalmic research and practice, and marking a notable advancement in the field.

Researcher(s)

• Promoter: Rozema Jos
• Fellow: Ghaderi Hosna

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Refractive errors are a collective definition for problems with focusing light accurately on the retina due to an aberrant shape of the eye and/or cornea. This leads to visual impairment if left untreated. They are currently treated with either wearables such as contact lenses or spectacles that may pose several disadvantages for patients such as discomfort, inadequate correction or (for lenses) an increased risk for eye infection. That is why there is a increasing trend towards refractive surgery for permeant vision correction, which range from laser ablative therapies to intraocular lens implantation. However, refractive surgeries are currently invasive, irreversible and limited to a certain degree of correction. We have developed a new treatment modality that can permanently correct refractive errors in a way that is personalized, non-invasive and reversible. In a previous IOF POC DEVELOP project, we confirmed our hypothesis on an in vitro level and initiated in vivo experiments, while this IOF POC LAUNCH project serves to deliver an in vivo safety and functional proof-of-concept rat animal model with improved chemical formulation. Furthermore, a financial and regulatory strategic plan will be established to increase the commercial readiness level.

Researcher(s)

• Promoter: Van den Bogerd Bert
• Co-promoter: Koppen Carina

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Spectrins are an integral part of the submembranous cytoskeleton providing both mechanical scaffolding and organization hub for other proteins in metazoan cells. The importance of spectrins to neuronal health is demonstrated by their association with a wide range of human neurological disorders (spectrinopathies). Currently, more than forty mutations in the gene encoding non-erythroid α-spectrin (SPTAN1) are associated with developmental and epileptic encephalopathies, hereditary motor neuropathy (HMN), spastic paraplegia (HSP), and ataxia. The underlying pathomechanisms remain largely unknown. In Drosophila, the highly conserved α-spec homolog similarly plays an important role in the nervous system development, as well as in synapse formation, its function and maintenance. Interestingly, synaptic defects associated with loss of α-spec can be suppressed via neuronal mitochondria repositioning. Conversely, increased levels of α-spec rescue a range of neuronal phenotypes linked to actin-dependent mitochondrial dysfunction in an α-synuclein neurodegeneration Drosophila model. These findings suggest that modulating the levels of α-spec in neurons might have an important and understudied impact on tuning mitochondrial dynamics and preserving neuronal health. Thus, the goal of my proposal is to deepen our knowledge on how neuronal actin and spectrin cytoskeleton regulate mitochondria and assess mitochondrial dysfunction at the basis of α-spectrinopathies, using Drosophila as a model organism. My project will provide insights on whether spectrin-associated mitochondrial dysfunction is a shared or specific feature for HMN, HSP and ataxia-associated spectrin mutants. I will deploy these findings to tailor a pharmacological treatment in the α-spectrinopathy neuronal cellular models and develop a therapeutic strategy.

Researcher(s)

• Promoter: Ermanoska Biljana

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

This innovation mandate aims to validate essential material properties of an innovative medical device that are crucial during surgery, both in the short and long term after the procedure. In this project, the focus is on basic research to further support the preliminary proof-of-concept. We have planned various qualification and validation experiments that the product must undergo, related to three phases: the procedure itself, short-term post-operation (the first four weeks), and long-term (months to years). Furthermore, market research is also conducted on two fronts. A roadmap is outlined for the preclinical development of the technology from the establishment of the spin-off, and a go-to-market strategy is being formulated. Using a SMART analysis, five parameters crucial to the functioning of the permanent contact lens were identified: shelf life, sterilization, laser impact, reversibility, and stability. This analysis forms the basis of the work packages of the basic research discussed in the project description.

Researcher(s)

• Promoter: Koppen Carina
• Fellow: Van den Bogerd Bert

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Despite receiving little attention, vestibular disorders result in loss of vestibular (inner ear) function and create costly health disparities. One-third of the population experiences some form of vestibular loss (VL) that presents with a mix of symptoms, from dizziness to brain fog, that reduces both quality of life and workforce capacity, and, for unknown reasons, is more prevalent and disabling in women. For most individuals with VL, the underlying etiology is unknown, and management is insufficient. Due to its prevalence, disability, and poor management, VL results in aggregated costs likely exceeding €6 billion per year in Europe. To combat the burden of VL and address the need for innovation along the entire chain, from basic knowledge to new treatments, we mobilize an international team of 13 academic and 9 non-academic partners who unite specialized scientific and clinical expertise, advances in computing, device engineering and remote management platforms, and clinical and patient networks. We synergize these resources to deliver state-of-the-art training necessary for 10 doctoral candidates (DCs) to innovate the new tools (knowledge, approaches, and devices) essential to understand the etiology of VL, capture and interpret (characterize) the relevant symptoms of VL, and expand treatments to restore vestibular function. With collaborative impact activities, we additionally train DCs to enable diverse end users to adopt, use, and further innovate these tools and stakeholders to better advocate for future innovation. By training new leading experts, we aim to advance patient-centered care of VL and, moreover, reduce healthcare costs and promote sustainable "green" healthcare systems while also enhancing workforce and innovation capacity for individuals with VL and in the emerging academic, clinical, and industrial sectors focused on the care of VL. PROVIDE will be a model for future networks tackling challenges in healthcare and striving for health equity.

Researcher(s)

• Promoter: Van Rompaey Vincent

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Chronic otitis media refers to a group of complex infectious and inflammatory diseases of the middle ear, causing permanent tympanic membrane perforations and conductive hearing impairment. Tympanoplasty and myringoplasty are commonly used surgeries to eradicate the disease and to reconstruct the eardrum. However, both strategies are associated with drawbacks including recurrent perforations, high capital investment, time-consuming quality control and limited availability of autologous graft tissue. A possible solution to address these issues is offered by the field of tissue engineering (TE). Although significant progress has been realized, there remain shortcomings related to current TE approaches including the lack of sufficient tympanic native tissue mimicry in terms of mechanical and morphological complexity. The aim of the current PhD research thus includes: (1) the development of 'clickable' poly-?-caprolactone- and gelatin-based building blocks containing photopolymerizable groups which can be applied as starting materials for the fabrication of 3D printed eardrums; (2) additive manufacturing of the 'clickable' building blocks via digital light processing and two-photon polymerization towards the creation of 3D printed eardrums; (3) in-depth characterization of the 3D printed constructs resulting in a profound understanding of the scaffolds' properties; (4) in vitro, in vivo and ex vivo evaluation of the artificial eardrums focusing on performance.

Researcher(s)

• Promoter: Van Rompaey Vincent

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

The corneal endothelium is the innermost layer of the human cornea, the eye's transparent window. A dysfunctional endothelium leads to corneal opacification, which is a common cause of corneal blindness worldwide and results in an unavoidable need for a transplantation. Unfortunately, the global donor shortage causes very long waiting lists. A pharmacological compound to stimulate in vivo corneal endothelial regeneration therefore is a very interesting alternative treatment to reduce the reliance on donor corneas. However, there are many limitations regarding the traditional drug discovery pipelines such as high cost and long development times. Moreover, the corneal anatomy hampers drug permeation. The aim of my PhD therefore is to tackle both these limitations so to deliver an innovative pharmacological treatment. Hence, this project proposes a high throughput biological screening of repurposed drugs, i.e. the screening of formerly approved compounds. This biological data will serve to develop and train a virtual compound screening model to predict additional potential lead compounds. The high throughput screenings together with a thorough characterization and optimalization of the physico-chemical properties of the main hits, will lead to the identification of one repurposed lead compound. Eventually, I will assemble this compound together with a corneal permeability enhancer into an inventive eye drop that facilitates corneal penetration to reach the endothelium.

Researcher(s)

• Promoter: Koppen Carina
• Co-promoter: Deben Christophe
• Co-promoter: Van den Bogerd Bert
• Fellow: Witters Charissa

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Hearing loss has a significant impact on quality of life and cognitive function, affecting more than 1.57 billion people worldwide. The application will focus on the autosomal dominant disorder DFNA9 which leads to post-lingual severe-to-profound sensorineural hearing loss (SNHL). DFNA9 is caused by heterozygous mutations in the COCH gene that lead to the formation of mutant cochlin. Currently, no treatment is available to prevent or cure SNHL in DFNA9. This application presents an innovative approach to go beyond the current state-of-art in the field of SNHL by in vivo evaluation of a disease-modifying gene therapy injected in the inner ear to downregulate expression of the mutant COCH allele. The applicant will do so by using lipid nanoparticles loaded with a CRISPR-nuclease optimized in vitro in a unique genetically humanized DFNA9 mouse model carrying the exact mutation of our human population. By sparing the normal allele, a heterozygous protein-truncating mutation will be created, which would not lead to a phenotype of SNHL. The application also presents an innovative approach to identify tissue-specific (perilymph) and blood-based bio-assays in humans and mice, that reflect tissue-specific pathophysiology only available in the mouse model. The discovery of these in vivo biomarkers will be a major breakthrough in the SNHL field and important to evaluate future disease-modifying therapies for DFNA9 at a molecular and biochemical level.

Researcher(s)

• Promoter: Van Rompaey Vincent
• Fellow: Van Rompaey Vincent

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Hearing loss has a significant impact on quality of life and cognitive function, affecting more than 1.57 billion people worldwide. The application will focus on the autosomal dominant disorder DFNA9 which leads to post-lingual severe-to-profound sensorineural hearing loss (SNHL). DFNA9 is caused by heterozygous mutations in the COCH gene that lead to the formation of mutant cochlin. Currently, no treatment is available to prevent or cure SNHL in DFNA9. This application presents an innovative approach to go beyond the current state-of-art in the field of SNHL by in vivo evaluation of a disease-modifying gene therapy injected in the inner ear to downregulate expression of the mutant COCH allele. The lab will do so by using lipid nanoparticles loaded with a CRISPR-nuclease optimized in vitro in a unique genetically humanized DFNA9 mouse model carrying the exact mutation of our human population. By sparing the normal allele, a heterozygous protein-truncating mutation will be created, which would not lead to a phenotype of SNHL.

Researcher(s)

• Promoter: Van Rompaey Vincent
• Co-promoter: Verdoodt Dorien
• Fellow: Sels Lize

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Spectrins are an integral part of the submembranous cytoskeleton providing both mechanical scaffolding and organization hub for other proteins in metazoan cells. The importance of spectrins to neuronal health is demonstrated by their association with a wide range of human neurological disorders (spectrinopathies). Currently, more than forty mutations in the gene encoding non-erythroid α-spectrin (SPTAN1) are associated with developmental and epileptic encephalopathies, hereditary motor neuropathy (HMN), spastic paraplegia (HSP), and ataxia. The underlying pathomechanisms remain largely unknown. In Drosophila, the highly conserved α-spec homolog similarly plays an important role in the nervous system development, as well as in synapse formation, its function and maintenance. Interestingly, synaptic defects associated with loss of α-spec can be suppressed via neuronal mitochondria repositioning. Conversely, increased levels of α-spec rescue a range of neuronal phenotypes linked to actin-dependent mitochondrial dysfunction in an α-synuclein neurodegeneration Drosophila model. These findings suggest that modulating the levels of α-spec in neurons might have an important and understudied impact on tuning mitochondrial dynamics and preserving neuronal health. Thus, the goal of my MSCA proposal is to deepen our knowledge on how neuronal actin and spectrin cytoskeleton regulate mitochondria and assess mitochondrial dysfunction at the basis of α-spectrinopathies, with a combined use of Drosophila as a model organism, and human iPSC-derived neurons as a platform to translate the findings to human neuronal health and disease. My project will provide insights on whether spectrin-associated mitochondrial dysfunction is a shared or specific feature for HMN, HSP and ataxia-associated spectrin mutants. I will deploy these findings to tailor a pharmacological treatment in the α-spectrinopathy neuronal cellular models and develop a therapeutic strategy

Researcher(s)

• Promoter: Baets Jonathan
• Fellow: Ermanoska Biljana

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Consumables budget in order to support the functioning of the IBB and the researchers associated with the UAntwerp who are affiliated or collaborate with the IBB, to be used to develop scientific activities.

Researcher(s)

• Promoter: Baets Jonathan

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Next Generation Sequencing technologies have accumulated genetic causes for Mendelian diseases, often without full insight into the cellular function of the gene involved. Conversely, patients with rare neurogenetic diseases are often lacking a genetic etiology. SPTAN1 (?-II-spectrin), a major cytoskeletal protein, is exemplary in this with a notably wide phenotypic spectrum but surprisingly little understanding of its molecular and cellular biology. Previously only associated with epilepsy and intellectual disability, we recently published novel mutations in SPTAN1 associated with Hereditary Motor Neuropathy and now also in Ataxia and Hereditary Spastic Paraplegia. ?-II-spectrin is the central component of the spectrin complex and is widely expressed in all cells but how its disturbances cause various neurological diseases is poorly understood. We will establish both cortical and motor neurons from patient-derived induced pluripotent stem-cells of three SPTAN1 mutations that are representative for the main associated diseases. Cytoskeletal abnormalities in these neurons will be studied using super-resolution microscopy, axonal transport assays and electrophysiological studies. Transcriptome-profiling of the neuronal cultures will allow to explore the interaction network of the spectrin complex. Ultimately, we will generate novel functional candidate genes that will be translated back to large genetic datasets of patients with diagnostically unresolved neurogenetic diseases.

Researcher(s)

• Promoter: Baets Jonathan

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

The corneal endothelium lies on the interior of the cornea, which is the window of our body. Proper function of this corneal endothelium is essential to obtain a crystal-clear cornea. Current consensus holds that endothelial cells do not display any significant regenerative capacity. Damaged or non-functional cells may consequently lead to corneal blindness. In this regard, stimulation of the regenerative capacity of the corneal endothelium is of exceptional importance in the search for new therapeutic possibilities. Furthermore, for in vitro biomedical research the culture of primary corneal endothelium is an extremely time-intensive process without full guarantee of cell expansion. In this project we intend to provide a solution for these issues by pharmacological stimulation of the regenerative capacity of corneal endothelial cells through re-orientation of available drugs. During this project various molecules will be subject to a tri-fold screening method (cellular, subcellular and molecular), which leads to the selection of a regenerative compound for corneal endothelial purposes. On the one hand, specific ROCK-inhibitors will be tested, given their growth potential within tissue regeneration. On the other hand, commercially available drug libraries will be screened for compounds with known activity for regenerative capacities.

Researcher(s)

• Promoter: Koppen Carina
• Co-promoter: Deben Christophe
• Co-promoter: Van den Bogerd Bert

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Hearing loss is the most frequently reported sensory deficit and affects 1.57 billion people worldwide. It has a significant impact on quality of life. Studies have identified a significant correlation between hearing status and cognitive abilities. Deafness Autosomal Dominant 9 (DFNA9) is a dominant hereditary disorder characterized by a progressive sensorineural hearing loss (SNHL) associated with bilateral vestibulopathy (BV). In this project, the applicant will evaluate hearing, vestibular and cognitive function in (pre-)symptomatic DFNA9 patients and in genetically humanized DFNA9 mice. Based on the statistical analysis of baseline (cross-sectional) data already gathered, the applicant hypothesizes that DFNA9 patients are at significant risk for incident cognitive decline. This application presents a novel approach to identify pathophysiological mechanisms of SNHL, BV and cognitive decline in a genetically engineered mouse model designed to mimic DFNA9 in humans. This model is unique in the field of hearing research and will allow us to investigate the therapeutic potential of any gene editing intervention intended for human use beyond the scope of this application. The expected outcome is important to society because it may identify DFNA9 patients at risk for cognitive decline. Subsequently, it will provide data from a genetically humanized mouse model essential to translate findings from fundamental research to clinically meaningful knowledge and clinical trials.

Researcher(s)

• Promoter: Van Rompaey Vincent
• Co-promoter: Van Dam Debby
• Fellow: Gommeren Hanne

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Hearing impairment is a major disability affecting communication and quality of life. Speech perception tests are essential to measure the functional use of hearing, and to determine the effectiveness of hearing aids and implants. However, these language-based tests are influenced by linguistic and neurocognitive skills. So far, there are no objective tests to accurately predict hearing abilities and not require active participation. This is especially troublesome for patients with insufficient language proficiency, children or cognitive impairment. The project team has developed a non-attentive and objective prediction model which correlates very well with speech perception in noise scores. This model uses electroencephalography to measure brain activity alterations caused by frequency changes. In this project we aim to validate this Acoustic Change Complex (ACC) prediction model in a large-scale external validation study. In this project we will first optimize the recording procedure for efficient clinical use, and then perform a diagnostic test accuracy study in patients with varying degrees of sensorineural hearing loss, to confirm the high predictive value of the ACC model and to assess its test-retest reliability. If this project proves that the ACC prediction model is an effective and reliable biomarker of speech perception, it will finally give audiologists and doctors a hearing evaluation tool, to be used in a population who needs their hearing the most as they are already struggling with their communication. These patients and the general population will directly benefit from this diagnostic advancement, as it can increase the accuracy of their hearing evaluations and improve access to adequate hearing rehabilitation.

Researcher(s)

• Promoter: Van Rompaey Vincent

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Malformations of cortical development (MCD) are a heterogenous group of brain malformations, which represent a significant burden for health care and society. Affected individuals suffer from drug-resistant epilepsy and varying degrees of intellectual and motor disability. Using current molecular techniques including SNP-array and whole exome sequencing (WES), over half of MCD cases remain unsolved. Factors contributing to the "unsolved" MCD cases include coding variants of unknown significance (VUS) in known MCD genes, non-coding variants in the known genes influencing splicing or gene expression as well as more complex mutation types (e.g., structural variants, copy number variants), urging the use of whole genome sequencing (WGS) for MCD genetic testing. However, this approach will inevitably lead to the identification of more rare variants of unknown significance (VUS) in known MCD genes. Finally, novel disease genes not previously linked to MCD are still to be discovered. In this project, we aim to establish of a gene-specific disease signature based on RNA-sequencing data that pinpoints the disease gene or pathway on which WGS-based variant analysis should be focused. The selected genes affect either the PI3K-AKT-mTOR pathway or microtubule dynamics, two major pathways involved in brain development. Furthermore, we aim to increase the diagnostic yield in MCD patients by integrating transcriptomics and WGS data of currently "unsolved" MCD cases, allowing the identification of additional variants of interest. Finally, we use the identified disease signatures in the validation of novel MCD candidate genes with similar pathophysiological mechanisms. The results of this project will guide the implementation of transcriptome analysis as another tool in the genetic diagnostic toolbox for MCD and hereby improve patient management and appropriate counseling of families.

Researcher(s)

• Promoter: Jansen Anna
• Co-promoter: Meuwissen Marije
• Fellow: Rosenblum Jessica

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Hearing loss (HL) is a growing problem in modern society, and is associated with an increased risk for social isolation and unemployment. Although the genetic basis of adult-onset HL is still largely elusive, heritability is suggested in 30-70% of cases. Lacking curative or preventive (genetic) treatments, hearing aids and cochlear implantation (CI) can relieve part of the burden of HL. However, the majority of patients with adult-onset HL still do not experience a satisfactory improvement of their auditory function with these devices. Furthermore, the outcome of CI in adult-onset cases is often less favorable as compared to CI in congenital HL cases. DFNA9, caused by mutations in the COCH gene, is amongst the best-studied forms of dominantly-inherited adult-onset HL. The c.151C>T (p.(P51S)) mutation likely occurred many generations ago, and is now estimated to cause adult-onset progressive HL and vestibular dysfunction in >1500 Dutch and Belgian individuals. The high prevalence of this founder mutation in our cohorts presents a unique opportunity to overcome the translational obstacles in the development of novel inner ear therapeutics. The adult onset of hearing loss provides a window of opportunity for therapeutic intervention. The large cohort of patients with the exact same mutation provide enough power for future clinical trials. The dominant inheritance pattern of DFNA9 implies that only one of the two gene copies (alleles) contains a mutation. These DFNA9 mutations in the COCH gene are all well-established to result in the production of toxic cochlin proteins that interfere with the function of the healthy cochlin proteins produced from the healthy allele. As such, a treatment that can block the formation of these toxic cochlin proteins has high therapeutic potential, especially when administered in an early stage of the disease. The remaining cochlin proteins produced from the healthy allele are sufficient for normal inner ear function. Recently published antisense oligonucleotides (AONs; small strands of synthetic DNA and RNA molecules) can specifically induce the degradation of c.151C>T mutant COCH transcripts, but not COCH transcripts resulting from the healthy allele (de Vrieze et al, Molecular Therapy – Nucleic Acids, 2021). In this project, we aim to further improve the efficiency and stability of our best-performing c.151C>T AON by introducing chemical modifications, and perform a series of pre-clinical validation studies in patient-derived stem cell models and a humanized DFNA9 mouse model. These data will provide a strong foundation for a swift translation of our AON treatment to future clinical trials. As there is virtually no prior art on the use of AONs to treat inner ear disorders, our studies are designed to also provide insights in the safety and feasibility of AONs a treatment paradigm of inner ear disorders in general.

Researcher(s)

• Promoter: Van Rompaey Vincent
• Co-promoter: Ponsaerts Peter

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Hearing impairment is the most frequent sensory deficit in the human population, affecting 440 million people worldwide, whereby loss of hearing and balance has a significant impact on quality of life and society. Hearing loss is also listed by the World Health Organization as a priority disease for research into therapeutic interventions to address public health needs. DFNA9 (DeaFNess Autosomal 9) is an autosomal dominant hearing disorder caused by a heterozygous gain-of-function mutation in the COCH gene (Coagulation Factor C Homology) and is characterized by progressive late-onset (3rd-5th decade) sensorineural hearing loss (SNHL) and deafness. Within Belgium and the Netherlands, there are >1000 patients affected by the p.P51S COCH mutation, who – in the current absence of a disease modifying therapy – will develop deafness. A promising approach to tackle the pathophysiological mechanism of DFNA9 and stop or delay the onset of SNHL is to introduce a CRISPR-Cas9-based therapy into the inner ear, delivered by an AAV vector to disrupt or downregulate the expression of (mutant) COCH. In this project, I will phenotype a newly established humanized DFNA9 mouse model and assess whether in vivo delivery of a CRISPR-nuclease using an AAV-based viral vector leads to specific disruption of COCH.

Researcher(s)

• Promoter: Van Rompaey Vincent
• Fellow: Verdoodt Dorien

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Hearing loss affects 1.57 billion people worldwide and has been listed by the World Health Organisation as a priority disease for research into therapeutic interventions. DFNA9 is the most frequent hereditary disorder in Belgium and the Netherlands causing hearing loss at 20-30 years and evolving towards deafness by 60-70 years. Currently, there is no therapy available. The aim of this project is to develop a gene therapy that can delay or stop the progression of DFNA9 in the pre-symptomatic window of opportunity. Only one of the two copies of the COCH gene (one inherited from either parent), is mutated in DFNA9 and encodes for a toxic protein that affects the aging inner ear. Our therapeutic approach is designed to specifically stop the production of this mutated COCH protein, leaving the patient only with healthy COCH proteins. Earlier research has demonstrated that one healthy COCH gene is sufficient for normal hearing. It is of vital importance that protein production from the healthy COCH gene is not affected. As mutant and healthy COCH only differ by a single nucleotide, high sensitivity and specificity is essential to specifically recognize the mutant COCH gene. To achieve this, we will adapt the genetic manipulation tool "CRISPR-Cas9". This project will provide insight in which approach is most suitable to safely and specifically block the production of mutant COCH proteins and will lay the foundation for continued (pre)clinical development towards clinical trials.

Researcher(s)

• Promoter: Van Rompaey Vincent

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

The cornea is the transparent window to the eye and as such, eye drops are an interesting route of drug administration. In this project, we propose the development of a 3D corneal cell model that can be used to investigate corneal drug interaction. Studies that aim to simulate the pharmacokinetics and toxicological properties of drugs are mainly based on oversimplified 2D monocultures or animal studies that suffer from interspecies differences. These limitations skew proper predictive power during preclinical drug investigation. We propose the development of a 3D corneal model that includes all three cell layers and integrated microfluidics to simulate relevant physiological flows such as the tear film. In this way, we reduce the need for animal studies, while simultaneously introducing the in vivo complexity of 3D cell environments. The materials used will be fabricated (photocrosslinkable biopolymers) and printed in-chip using 2PP bioprinting that can simultaneously integrate corneal cells. The interfaces between materials and corneal cells are characterized in depth using molecular spectroscopy techniques, while detailed protein expression of cells in the 3D ECM are benchmarked to ex vivo cadaveric donor corneas with proteomics. TEER, flow rate and cell viability will be measured real-time by integrated sensors. The project finally aims for a proof-of-concept to determine permeability coefficients of common ocular drugs in the fully assembled 3D cell culture chip.

Researcher(s)

• Promoter: Koppen Carina
• Co-promoter: Van den Bogerd Bert

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

This project will identify previously unknown proteins in auditory hair cells and characterize their function. The outcomes will provide useful knowledge for the development of therapeutic approaches for hearing impairment. The auditory hair cells are found in the organ of Corti (in the inner ear). These cells are specialized sensory cells that transduce auditory signals into an electrical signal that is sent to the brain. Some of the proteins involved in auditory hair cell functioning are already identified by classical genetic approaches - via identification of causative genes in patients with hearing impairment or via mouse models. However, the majority of proteins involved in critical complexes for hearing remains unidentified. This project will identify new components of the lower tip-link complex in the organ of Corti with affinity purification (AP) followed by mass spectrometry (MS). The latest evolutions in proteomic techniques resulting in a gain in MS sensitivity now make this possible for the first time. Our preliminary data confirms the feasibility of this AP-MS approach for the hair cell complexes. New components will be identified and for a selection of these the molecular interactions with other proteins of the complex will be analysed in-depth. Additionally, we will identify the location of these proteins in the hair cells and their effect of ablation on hearing.

Researcher(s)

• Promoter: Baggerman Geert
• Promoter: Van Rompaey Vincent
• Co-promoter: Van Wielendaele Pieter

Research team(s)

• Translational Neurosciences (TNW)
• Ecosphere

Project type(s)

• Research Project

Abstract

The cornea is a barrier that protects the eye from the outside world and likewise hampers drug absorption. Most ophthalmic medicine is washed away during instillation and is absorbed into systemic circulation. This is especially relevant when considering the main target population, the elderly, which also have an increased susceptibility to adverse drug reactions due to polypharmacy and decreased renal function. Hence, new topical formulations require rigorous testing to ensure therapeutic efficacy, while keeping local and systemic toxicity to a minimum. However, promising preclinical results are often not corroborated during human testing because available corneal models have poor predictive power. Traditional 2D culture fails to recapitulate complex tissues such as the cornea while animal models exhibit interspecies differences that limit translatability of results to humans. Organs-on-chips, which are rationally-designed microfluidic chips that contain artificial tissue, hold the promise of improving the status quo. While organ-on-chip technology has already proven its merits in certain fields, in the context of the cornea it remains relatively unexplored. This project proposal outlines the development of the first cornea-on-chip that comprises every cellular layer – epithelium, stroma and endothelium – of the cornea, exposed to the dynamics of an artificial tear film on one side and connected to an artificial anterior chamber on the other.

Researcher(s)

• Promoter: Koppen Carina
• Co-promoter: Van den Bogerd Bert
• Fellow: Van Meenen Joris

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

The cornea is a multi-layered and transparent membrane that focusses incoming light on the lens. One of the layers is the endothelium, which is a monolayer of corneal endothelial cells (CEnCs) responsible for the clarity of the cornea. Several diseases can cause damage to this monolayer which might result in visual impairment or blindness. Corneal blindness is the 4th cause of blindness, affecting more than 10 million people worldwide. The main treatment comprises a corneal transplantation. However, there is a severe donor shortage since only 1 donor cornea is available for 70 people on the waiting list. The aim of this PhD proposal is to overcome the limitations regarding the low donor availability by developing a suitable donor tissue independent implant that can restore the endothelium. To this end, membranes will be produced on which lab-grown CEnCs will be seeded, after which the entire implant will be implanted into the cornea and restore its transparency. To develop a cell interactive and transparent scaffold that is strong enough for implantation, multiple approaches will be investigated and their performance will be compared. Single- and double-layered membranes that are cell interactive and mechanically strong enough will be produced. The required cell-interactivity will be provided by modified gelatines while poly(D,L-lactic acid) or poly (styrene-co-maleic anhydride) are chosen for their structural integrity.

Researcher(s)

• Promoter: Koppen Carina

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

In the coming years the VOLANTIS research group, plans to conduct several studies related to visual optics and ocular biomechanics. Overall, these studies may be grouped into three topics. The first is refractive development and eye modelling, which studies how the eye grows and how this can be described as a mathematical model. Such models will look at e.g. how during eye growth the different components of ocular biometry interact with each other to first bring the eye in focus ('emmetropia') and then maintain this condition as the eye continues to grow. Other studies look at what happens if such a balance is disrupted or how it is accomplished in pathological eyes (e.g. premature infants or infants operated for cataract). Within the European OBERON project, we will also develop a new type of model that combines the biomechanics of the eye with its optical function as a platform for testing new treatments in virtual clinical trials. This 'opto-biomechanical' model will need close interactions with our European partners. The next study topic is keratoconus, a disease that gradually deforms the cornea, leading to a considerable loss in visual quality. Early detection of the disease and its possible progression is very important in its management as it allows the patients to preserve a higher visual quality through timely treatment. To this end, we are working on machine learning systems that can tell ophthalmologists whether an eye has keratoconus and, if so, if it is in a progressive state. Another project looks at improving the popular 'crosslinking' treatment that increases corneal elasticity and stops the progression. To do this, we need to develop corneal elasticity maps that can inform ophthalmologists what areas of the cornea need treatment. Although the current methods to develop such maps are very computationally intensive, we will use new methods that have not yet been tried to speed up this process from several hours to minutes, making it clinically useful. Finally, we will study straylight and dark adaptation, which refers to being blinded by bright lights ('glare') and the time needed to recover afterwards. These phenomena can play a major role in traffic safety as drivers may be blinded by the headlights of oncoming cars. Since it is not yet understood at what level of glare the safety risks for safe driving become too high, we will organize a study to test the effect of a bright light source on performance in a driving simulator in a darkened room. The outcomes of these experiments will later be formulated as advice to legislative authorities to improve traffic safety.

Researcher(s)

• Promoter: Rozema Jos
• Fellow: Rozema Jos

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Stroke incidence is increasing and, consequently, so are the number of motor impaired survivors. Whereas patient tailored rehabilitation strategies are believed to greatly improve recovery, a reliable biomarker for gait outcome prediction that enables such patient tailored rehabilitation is currently missing. Therefore, this project aims to explore whether brain structural connectivity between areas responsible for gait can be used as a biomarker for gait recovery prediction. This will be done by characterizing brain connectivity during the first 6 months after stroke using diffusion magnetic resonance imaging (dMRI) and correlating these findings with gait recovery as measured by a comprehensive gait analysis. Brain connectivity will be assessed considering 12 brain areas and 18 white matter pathways between them. Gait analysis will include data on kinetics, kinematics and muscle activity. All results will be used for a machine learning protocol composed by network-based statistics and deep learning As such, when a correlation can be established, the dMRI assessment of connectivity could serve as a biomarker to guide rehabilitation strategies, early in the course of recovery, so that rehabilitation outcome can be improved.

Researcher(s)

• Promoter: Yperzeele Laetitia
• Co-promoter: Saeys Wim
• Fellow: Van Hinsberg Amber

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Sporadic Inclusion Body Myositis (sIBM) is the most common myopathy above the age of 50 years and is presumed to be an acquired disorder. The interplay of potential mechanisms underlying sIBM pathogenesis remains unclear as is illustrated by a dual inflammatory-degenerative pathology in the affected muscle. Due to lack of effective therapy, steady decline of muscle strength results in loss of ambulation and ultimately reduced life expectancy. The uncertainty concerning the key pathomechanisms complicates the design of reliable experimental cell- or animal-models, emphasizing the relevance of well-designed experiments using human disease tissue. Capitalizing on the availability of patient disease-tissue under the form of diagnostic muscle biopsies, we established a unique (in house performed) high-resolution proteomics study, assessing the proteome of muscle lysates of 28 sIBM patients and 28 matched control individuals. This dataset provided unique insights in the proteomic landscape of sIBM, captivating known core features of sIBM pathomechanisms as well as highlighting strong signatures pointing towards selective failure of myogenesis. We identified KDM5A as a key upstream driver of sIBM pathology, interconnecting the DNA damage pathway, regulation of cell cycle and differentiation and energy homeostasis in sIBM skeletal muscle. The central aim of this project is to gather additional functional evidence that upregulation of KDM5A, a histone demethylase, is involved in sIBM pathomechanisms and failure of muscle regeneration in particular. Ultimately, the aim is working towards an actual therapy for sIBM, a currently untreatable and debilitating muscle disorder. Firstly, we will study KDM5A expression and activity and afterwards inhibition of KDM5A in immortalized human myoblast cell line with induced sIBM-like pathology. Secondly, we will study the effect of KDM5A overexpression in immortalized human myoblast cell lines from healthy middle-aged control individuals. Ultimately, we will establish immortalized patient-derived myoblasts from muscle as well as from induced Pluripotent Stem Cells (iPSC) and study the effect of KDM5A inhibition. This project could have major impact on the sIBM research field, by: 1) providing new mechanistic insights based on an alternative in vitro model not biased towards one of two general hypotheses; 2) resulting in a novel therapeutic strategy for sIBM. Furthermore, we aim to establish sIBM patient-derived immortalized myoblasts and iPSC differentiated into myotubes as a novel tools for further in vitro pathomechanistic and therapeutic studies.

Researcher(s)

• Promoter: Baets Jonathan
• Fellow: de Vries Geert

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Tinnitus is a common symptom that affects 10 to 15% of the adult population, causing mood changes, anxiety, depression, sleep disorders, concentration problems and other psychological/emotional issues leading to severe disruptions to the quality of life. Tinnitus does not represent a disease itself but instead is a symptom of a variety of possible underlying diseases or malfunctions making the tinnitus population very heterogeneous. In this project we address one specific subtype, being somatic tinnitus. In somatic tinnitus, the tinnitus is influenced by dysfunctions of the cervical spine and/or temporomandibular area, such as: increased muscle tension or mobility limitations. The content of the state-of-the-art therapy for somatic tinnitus is well established, but the implementation in clinical practice is not ideal yet. The current standard physiotherapy treatment, including manual mobilizations and exercises that are mostly performed at home, is perfectly implementable, but patients often do not perform home exercises or do them incorrectly. Furthermore, physiotherapists often lack knowledge about tinnitus in general, what makes it very hard for them to provide the correct tinnitus counselling that should be part of the somatic tinnitus therapy. To overcome these hurdles, a smartphone application was developed by the consortium partners, that provides tinnitus counselling through a chatbot function. The application also contains an exercise program, with daily reminders and videos to show how the exercises should be performed correctly. This application was tested by a panel of 30 tinnitus patients for user-friendliness and willingness-to-use, but the effectiveness of the application as part of a blended physiotherapy intervention still needs to be evaluated. Furthermore, our project aims to investigate the cost-effectiveness of this blended physiotherapy program compared to the current standard care.

Researcher(s)

• Promoter: Van Rompaey Vincent

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Keratoconus is an eye disease in which the cornea gradually deforms, which causes the patients to experience a rapidly deteriorating visual quality. Early detection and follow-up of this disease is therefore very import as it allows for a quick therapeutical intervention. Recently, the Visual Optics Lab Antwerp (VOLANTIS) has developed new computational methods to monitor the structural changes in the cornea and to provide the best possible optical correction. The goal of this project is to expand on these methods, as well as to apply them to a large amount of previously collected patient data. This way we want to improve the prospects of patients by allowing to retain the highest possible quality of life.

Researcher(s)

• Promoter: Rozema Jos
• Fellow: Francis Sharon

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

The eye is a biological tissue with optical and biomedical properties that govern the way the eye refracts light, focuses that light onto the retina and can dynamically alter that focus over a range of distances. This impressive flexibility results from the delicate way in which the mechanical properties of the eye very precisely affect its optics. These properties vary considerably between individuals and can alter over time in response to visual demands, as well as with eye growth, ageing and pathology. The origins of these biomechanical changes over time are very poorly understood, however, and point at a need for answers, given the increase in life expectancy and in societal demands for high quality vision. To address these issues, we present the first European collaboration that brings together a group of scientists that work on the optics and biomechanics of the eye, cover a broad range of disciplines and skills. This highly interdisciplinary consortium will also create a training network to give young researchers the opportunity to learn from renowned experts on ocular opto-mechanics, share their learning experiences and take advantage of placements in Universities, hospitals and industry. This will give them a wide and novel skill set to translate their research to scientific, industrial, or clinical applications, such as a new generation intraocular implants for cataract surgery, biologically relevant eye models that mimic the eye at any age, and novel treatment therapies that can control, reduce or ultimately prevent refractive error from occurring. These anticipated innovations will lead to wide-reaching and pioneering advances to enhance our understanding of the interrelationship between ocular optics and biomechanics. From this, the young researchers will emerge with multi-disciplinary, versatile skills, be highly employable, able to address skills shortages, be leaders in vision science and pioneer new industries in optical design and modelling.

Researcher(s)

• Promoter: Koppen Carina
• Co-promoter: Rozema Jos

Research team(s)

• Translational Neurosciences (TNW)

Project website

Project type(s)

• Research Project

Abstract

Neuromuscular disorders (NMD) are diverse, usually inheriteddisorders that are chronically debilitating with tremendous societalimpact. We will focus on Hereditary Motor Neuropathies (HMN) andInherited/ Idiopathic Muscle Diseases (IMD). The unmet needs are"missing heritability" and lack of patho-mechanistic understandingand effective therapies. First, we will identify novel genetic causes ofHMN/IMD through advanced genetic studies in large patient cohortswithin international consortia. This allows the identification of rarecauses and unconventional mutation mechanisms. Secondly, basedon our recent identification of α-spectrin mutations in HMN we willstudy the associated spectrum of neuro-spectrinopathies. We willapply advanced machine learning techniques to a custom-builtdatabase featuring known and novel mutations. This will drivemutations modelling in patient derived induced pluripotent stem cellsin order to unravel the roles of the neuronal spectrin-cytoskeleton.Thirdly we will design novel therapies for idiopathic muscle disease,the most important being sporadic inclusion body myositis (sIBM).Using high-resolution proteomics techniques, we found that a keyupstream regulator driving the pathology is KDM5A, a histonedemethylase that induces failure of muscle regeneration in sIBMmuscle. We will use preclinical validation in cellular models to studytherapeutic KDM5A inhibition (pat. pend.) and will seek strategicindustry partners to develop this further.

Researcher(s)

• Promoter: Baets Jonathan
• Fellow: Baets Jonathan

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

The corneal endothelium is the interior of the cornea, comparable to the window through which our body looks at the outside. Proper function of this corneal endothelium is essential to obtain a crystal- clear cornea. Current consensus holds that endothelial cells do not display any significant regenerative capacity. Damaged or non-functional cells may consequently lead to corneal blindness. In this regard, stimulation of the regenerative capacity of the corneal endothelium is of exceptional importance in the search for new therapeutic possibilities. On the one hand, these alternative strategies will spare transplantable corneal endothelial donor tissue which will be beneficial for visually impaired patients in terms of shorter donor waiting lists. Furthermore, a regenerative compound could be used as a supplementary treatment in corneal endothelial surgery or in the development of novel cell therapies. On the other hand, for in vitro biomedical research the culture of primary corneal endothelium is an extremely time-intensive process without full guarantee of cell expansion. Stimulation of the regenerative capacity of primary tissue would therefore increase the amount of available starting material for in vitro research, thereby drastically improve the translatability of basic ophthalmological research. In this project we intend to provide a solution for these issues by pharmacological stimulation of the regenerative capacity of corneal endothelial cells through ROCK inhibitors (ROCKi), given their growth potential within tissue regeneration. However, there is no golden standard ROCKi available yet to boost corneal endothelial regeneration that is rationally described and characterized for this purpose, which leaves space for improved compound characterization. In this project, customized ROCK inhibitor libraries, containing inhibitors with different IC50 values and variable selectivity to its key target proteins will be screened. As such we will characterize the regenerative capacity of those compounds in terms of proliferation and migration processes. During this project all the ROCKi will be subject to a two-fold screening method, creating an innovative drug repurposing pipeline. This screening setup is based on the synergy of high throughput live cell imaging and genomic analysis (i.e., RNA sequencing and kinomics) to connect the cellular to the subcellular level. Live cell imaging applied on the different ROCKi will generate kinetic drug profiles and will indicate the most efficient timepoint for downstream genomic analysis. In its turn, these genomic sequencing techniques provide tremendous insights for unravelling activated pathways and signaling molecules. The combination of cellular and subcellular compound characterization will result in the selection of the most promising ROCKi for hit-to-lead optimization for corneal endothelial regeneration purposes.

Researcher(s)

• Promoter: Vercammen Hendrik

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Keratoconus is a progressive disease of the cornea that is characterized by corneal thinning and outward bulging in the shape of a cone. This leads to visual impairment if left untreated. A range ofsoft to hard contact lenses are commercially available for visual corrections, but they become inadequate or uncomfortable after prolonged wear or in case of disease progression. The second-line treatment consist of corneal crosslinking or transplantation, but these often still require corrective lenses afterwards. We have developed a new treatment modality for keratoconus patients that can permanently correct their vision and is non-invasive and reversible. In a previous IOF POC CREATE project, we confirmed our hypothesis on an in vitro level, while this IOF POC DEVELOP project serves to deliver an in vivo safety and functional proof-of-concept in a mouse and rabbit animal model respectively. Furthermore, a thorough business plan will be further drafted with the emphasis on a regulatory roadmap and a quantitative market analysis.

Researcher(s)

• Promoter: Van den Bogerd Bert
• Co-promoter: Ni Dhubhghaill Sorcha

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Sporadic Inclusion Body Myositis (sIBM) is the most common myopathy above the age of 50 years and is presumed to be an acquired disorder. The interplay of potential mechanisms underlying sIBM pathogenesis remains unclear as is illustrated by a dual inflammatory-degenerative pathology in the affected muscle. Due to lack of effective therapy, steady decline of muscle strength results in loss of ambulation and ultimately reduced life expectancy. The uncertainty concerning the key pathomechanisms complicates the design of reliable experimental cell- or animal-models, emphasizing the relevance of well-designed experiments using human disease tissue. Capitalizing on the availability of patient disease-tissue under the form of diagnostic muscle biopsies, we established a unique (in house performed) high-resolution proteomics study, assessing the proteome of muscle lysates of 28 sIBM patients and 28 matched control individuals. This dataset provided unique insights in the proteomic landscape of sIBM, captivating known core features of sIBM pathomechanisms as well as highlighting strong signatures pointing towards selective failure of myogenesis. We identified KDM5A as a key upstream driver of sIBM pathology, interconnecting the DNA damage pathway, regulation of cell cycle and differentiation and energy homeostasis in sIBM skeletal muscle. The central aim of this project is to gather additional functional evidence that upregulation of KDM5A, a histone demethylase, is involved in sIBM pathomechanisms and failure of muscle regeneration in particular. Ultimately, the aim is working towards an actual therapy for sIBM, a currently untreatable and debilitating muscle disorder. Firstly, we will study KDM5A expression and activity and afterwards inhibition of KDM5A in immortalized human myoblast cell line with induced sIBM-like pathology. Secondly, we will study the effect of KDM5A overexpression in immortalized human myoblast cell lines from healthy middle-aged control individuals. Ultimately, we will establish immortalized patient-derived myoblasts from muscle as well as from induced Pluripotent Stem Cells (iPSC) and study the effect of KDM5A inhibition. This project could have major impact on the sIBM research field, by: 1) providing new mechanistic insights based on an alternative in vitro model not biased towards one of two general hypotheses; 2) resulting in a novel therapeutic strategy for sIBM. Furthermore, we aim to establish sIBM patient-derived immortalized myoblasts and iPSC differentiated into myotubes as a novel tools for further in vitro pathomechanistic and therapeutic studies.

Researcher(s)

• Promoter: Baets Jonathan

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Hearing impairment is the most frequent sensory deficit in the human population, affecting 440 million people worldwide, whereby loss of hearing and balance has a significant impact on quality of life and society. Hearing loss is also listed by the World Health Organization as a priority disease for research into therapeutic interventions to address public health needs. DFNA9 (DeaFNess Autosomal 9) is an autosomal dominant hearing disorder caused by different heterozygous gain-of-function mutations in the COCH gene (Coagulation Factor C Homology) and is characterized by vestibular dysfunction and progressive late-onset (3rd-5th decade) sensorineural hearing loss (SNHL) leading to deafness. Within Belgium and the Netherlands, there are >1000 patients affected by the p.P51S COCH mutation, one of the heterozygous mutations causing DFNA9, who – in the current absence of a disease modifying therapy – will develop deafness. A promising approach to tackle the pathophysiological mechanism of DFNA9 and stop or delay the onset of SNHL is to introduce a CRISPR-Cas9 mRNA based therapy into the inner ear, delivered by a Lipid nanoparticle (LNP) to disrupt or downregulate the expression of mutant COCH protein. Until today, most researchers focus on the use of viral vectors, mostly AAV, to apply gene therapy in vivo in the inner ear. However, many people have already been exposed to AAV earlier in life and generated specific antibodies. Therefore, using LNP could provide a suitable alternative as they are already been proven to be safe when injecting a large population (COVID-19 mRNA vaccines). Moreover, using Cas9 mRNA instead of Cas9 DNA will only lead to a temporary expression of the Cas9 protein which will largely decrease the change on an evoked immune response against Cas9. To develop a cochlear gene therapy than can be translated to a human setting, a highly innovative humanized DFNA9 mouse model was generated. These mice bear humanized COCH harbouring the p.P51S mutation and thus mimic the genotype of DFNA9 patients. The goal of this project is: (1) assessing the safety and targeted delivery of LNP injected in vivo in the inner ear of our humanized DFNA9 mouse model (2) assess the use of LNP for in vitro delivery of Cas9/gRNA complexes to specifically downregulate the production of mutant cochlin in embryonic fibroblasts derived from our humanized DFNA9 mouse model.

Researcher(s)

• Promoter: Verdoodt Dorien

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

International guidelines for clinical voice assessment state that auditory-perceptual evaluation of voice quality is an essential dimension of the assessment. It is a holistic, quick, cost-effective and non-invasive evaluation method. Worldwide the GRBAS scale (Hirano, 1981) is used to rate voice quality, in which 5 parameters of dysphonia (Grade, Roughness, Breathiness, Astenicity and Strain) are scored on a four-point scale. Despite the advantages of perceptual evaluation, variability within and between raters is a problem. Research has shown that training with anchor voices leads to a more accurate and consistent assessment of voice quality, but no freely available training programs or online training tools with an incorporated voice samples database exist to date (Walden, 2020). This research project aims to improve the quality and standardization of auditory perceptual evaluation of voice, on the one hand by determining anchor voices based on inter- and intra-rater agreement, on the other hand by developing an online training module. Subsequently, the effect of online training with anchor voices is evaluated on both students and experienced clinicians.

Researcher(s)

• Promoter: Van Nuffelen Gwen

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

In this project, the main objective is to investigate the evolution of hearing levels and speech understanding in carriers of the P51S mutation in the COCH gene. This autosomal dominant disorder, known as DFNA9, is characterized by a progressive decline of hearing and vestibular function and will eventually lead to deafness and vestibular loss. No cure is currently available for DFNA9. The optimal therapeutic approach would be to prevent the onset of symptoms, e.g. by developing genetic therapies to target and block the mutation. Because longitudinal data on hearing function within this population are lacking, the applicant has already gathered prospective data to increase our understanding of its evolution. More specifically, the recently identified effect of sex on the natural evolution of hearing levels and speech understanding, and interaural differences will be studied using the complied dataset. These results will be essential for the design of future clinical trials studying disease-modifying therapies. Currently, DFNA9 patients can be rehabilitated with hearing aids and cochlear implants but this leads to a variable outcome with respect to speech understanding. For this reason, our third objective is to investigate the neural reserve in a cohort of cochlear implant users with DFNA9 by using electrically-evoked compound action potentials (ECAP's). By doing so, we will evaluate the responsiveness of the auditory nerve and measure the implications for speech perception.

Researcher(s)

• Promoter: Van Rompaey Vincent

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Obstructive sleep apnea (OSA) is a highly prevalent disease, associated with several cardiovascular and cerebrovascular comorbidities. Adequate treatment is thus crucial. Based on the current guidelines, continuous positive airway pressure (CPAP) is considered the standard OSA treatment. While CPAP efficacy is high, patient tolerance and acceptance is only moderate. In general, alternative non-CPAP treatments like mandibular advancement devices, hypoglossal nerve stimulation or pharmacotherapy are well-received, however, their efficacy is potent in some patients but incomplete in others. Efficacy of emerging therapies depends largely on the site of obstruction of the upper airway, key diagnostic information that is notoriously challenging to obtain. In current clinical practice this information is captured during drug-induced sleep endoscopy (DISE), assessing the upper airway during sedation. However, this DISE procedure still requires an additional step in the clinical path involving specialized personnel, time and equipment at the operating theatre. Therefore, I aim to 1) correlate the collapse patterns during DISE with parameters extracted from baseline clinical data in order to develop a prediction model to predict collapse patterns without the need of drug-induced sedation and 2) to apply this model to patients treated with a non-CPAP treatment. In this way, I aim to attain precision OSA medicine using endotype-driven instead of guideline-based OSA treatment.

Researcher(s)

• Promoter: Vanderveken Olivier
• Co-promoter: Braem Marc
• Co-promoter: Verbraecken Johan
• Fellow: Op de Beeck Sara

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Next Generation Sequencing (NGS) technologies have resulted in the accumulation of a large amount of genetic causes for Mendelian diseases, with often no clear-cut link or evident cellular function correlating to the phenotype available. Conversely, a multitude of patients with Rare Diseases, of which many suffer from neuropathies, are lacking a genetic etiology. SPTAN1 (?-II-spectrin) provides an excellent example of this, with a notably high phenotypical heterogeneity but surprisingly little known about its molecular biology and cellular functions. Previously only associated with epilepsy and intellectual disability, we recently published novel mutations in SPTAN1 associated with Hereditary Motor Neuropathy (HMN). Furthermore, our own unpublished data show patients with ataxia and Hereditary Spastic Paraplegia (HSP), widening the phenotypical spectrum even further. I set out to uncover the molecular causes of the phenotypical heterogeneity present in SPTAN1, starting with the curation of an extensive database of SPTAN1 mutations and their associated phenotypes. Leveraging the information contained in this database through the use of machine learning techniques, I will perform experiments in carefully chosen patient-derived induced Pluripotent Stem Cells (iPSCs) that will allow the uncovering of differential effects between variants in SPTAN1 and their associated phenotypes, yield novel candidate genes for such disorders and teach us about the patho-biology of spectrins.

Researcher(s)

• Promoter: Baets Jonathan

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Speech rehabilitation in persons with a (chronic) speech disorders like dysarthria is very demanding and requires a lot of time and financial means. Speech technology based solutions offer an interesting supplementary opportunity. In this project which started within a European H2020 project, a Virtual Articulation Therapist (VAT) is build and further clinically operationalised. Different neural networks were trained in collaboration with partners from the TAPAS consortium (https://www.tapas-etn-eu.org/) to allow a precise phoneme identification and detailed phoneme error detection. The developed algorithms were integrated in a friendly user interface to allow patients to train themselves in their own environment. The VAT will be further evaluated with samples of healthy speakers and speakers with dysarthria on feasibility, acceptability and effectiveness. Next to the development of the VAT, acoustic features of accent production are explored to support perceptual evaluation of dysarthric speech. Both articulation and prosodic features like word accent play an important role in speech intelligibility.

Researcher(s)

• Promoter: Van Nuffelen Gwen
• Fellow: Mendoza Ramos Viviana

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

SPTAN1 (α-II-spectrin) is the sole α-spectrin subtype in the nervous system and has a critical function in neuronal development and homeostasis. Intriguingly, mutations in SPTAN1 display a strikingly high degree of phenotypical heterogeneity. Previously only associated with epilepsy and intellectual disability, we recently published novel mutations in SPTAN1 associated with Hereditary Motor Neuropathy (HMN). We now have additional preliminary evidence that implicates SPTAN1 variants in both ataxia, Hereditary Spastic Paraplegia (HSP) as well as myopathy, highlighting the relevance of SPTAN1 mutations in rare neurological and (neuro)muscular diseases. In this project we will investigate the novel link between SPTAN1 mutations and ataxia phenotypes by: (1) investigating one specific recurrent variant; (2) identifying additional pathogenic variants using a multiplex PCR screening method and; (3) using patient-derived cells to investigate a.o. mRNA and protein expression levels. Doing so we aim to establish ataxia as a novel phenotype within SPTAN1 related diseases and explore fundamental cellular characteristics of ataxia associated SPTAN1 mutations.

Researcher(s)

• Promoter: Baets Jonathan

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

The corneal endothelium is the most inner layer of the human cornea, the window of the human eye. This cell layer is of utmost importance, since it functions to maintain corneal transparency. Upon damage to the endothelium, corneal oedema ensues and subsequently, visual impairment. The only solution for these patients is to transplant a new, functional corneal endothelium sourced from a donor eye. However, on a worldwide scale there are not enough donor corneas to meet for the patients in need. Not only does this shortage result in long waiting lists, but this donor scarcity also hinders corneal endothelial research. The limited tissue supply make research time-consuming, but also the corneal endothelial cells are very difficult to bring in culture. That is why until this very day the pathophysiology of corneal endothelial diseases remains to be elucidated. In this project I propose the reversible immortalization of corneal endothelial cells to overcome both the worldwide donor shortage and the intricate ex vivo growth. The process of reversible immortalization consists of four different steps: 1) insertion of removable genes to stimulate proliferation, (2) positive selection of transfected cells, (3) gene excision and (4) an additional negative selection to eliminate any residual engineered cells. In this small research project, I will investigate to establish the first three steps using either a lentiviral vector or a transposon system. The final aim is to effectively use the transposon system, while lentiviruses are part of this application as a positive control, since protocols and results are found throughout the literature, but are scarce for PiggyBac. However, the PiggyBac displays the intrinsic advantage such as a finger-print free excision of a transgene. Upon success, we can easily create vast amounts of corneal endothelial cells in our laboratory. These cells can will feed into our established projects of developing a corneal endothelial cell therapy or the development of a so-called cornea-on-a-chip.

Researcher(s)

• Promoter: Van den Bogerd Bert

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Unraveling genotype-phenotype correlations in diseases associated with SPTAN1 SPTAN1 (alpha-II-spectrin) plays an essential role in neuronal development and homeostasis, as it is the only alpha spectrin subtype present in the nervous system. Mutations in SPTAN1 were initially associated with a spectrum of epilepsy phenotypes. However, recent studies have shown that a wide variety of neurological phenotypes, including hereditary motor neuropathies, hereditary spastic paraplegia and possibly ataxia, can be attributed to mutations in SPTAN1. At present, there is no clear idea of ​​the underlying pathogenetic mechanism involved for each of the phenotypes, nor of the existence of other modifiers involved that influence this clinical heterogeneity. As such, this project aims to collect a large number of patients carrying SPTAN1 mutations and various phenotypes in order to unravel the common and specific mechanisms of diseases associated with SPTAN1. More specifically, a new analysis of the WES / WGS data available within the framework of international collaborations will be carried out in order to create a representative and uniform SPTAN1 catalog. Ultimately, patient-derived iPSC cell lines will be generated in the hope of uncovering the complex mechanisms underlying phenotypic heterogeneity. The bioinformatic, statistical and histological analysis of the SPTAN1 catalog will allow a better understanding of the different genotype-phenotype correlations, which will be very useful in determining the mutations to be best modeled in iPSC cell lines derived from the patient.

Researcher(s)

• Promoter: Baets Jonathan

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Site, pattern and degree of upper airway collapse is correlated with different obstructive sleep apnea (OSA) treatment outcomes. Currently, assessment requires additional, invasive endoscopy techniques. In the current research proposal I aim to non-invasively associate endoscopic outcomes with baseline overnight sleep study parameters using the technical and analytical skills from the group of Drs. Wellman and Sands at Harvard Medical School and the high quality clinical data of the Antwerp University Hospital. Combining the unique features of both groups into one research project will leverage sleep medicine in both the US and Belgium, paving the way to personalized OSA management.

Researcher(s)

• Promoter: Vanderveken Olivier
• Fellow: Op de Beeck Sara

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Next Generation Sequencing (NGS) technologies have resulted in the accumulation of a large amount of genetic causes for Mendelian diseases, with often no clear-cut link or evident cellular function correlating to the phenotype available. Conversely, a multitude of patients with Rare Diseases, of which many suffer from neuropathies, are lacking a genetic etiology. SPTAN1 (?-II-spectrin) provides an excellent example of this, with a notably high phenotypical heterogeneity but surprisingly little known about its molecular biology and cellular functions. Previously only associated with epilepsy and intellectual disability, we recently published novel mutations in SPTAN1 associated with Hereditary Motor Neuropathy (HMN). Furthermore, our own unpublished data show patients with ataxia and Hereditary Spastic Paraplegia (HSP), widening the phenotypical spectrum even further. I set out to uncover the molecular causes of the phenotypical heterogeneity present in SPTAN1, starting with the curation of an extensive database of SPTAN1 mutations and their associated phenotypes. Leveraging the information contained in this database through the use of machine learning techniques, I will perform experiments in carefully chosen patient-derived induced Pluripotent Stem Cells (iPSCs) that will allow the uncovering of differential effects between variants in SPTAN1 and their associated phenotypes, yield novel candidate genes for such disorders and teach us about the patho-biology of spectrins.

Researcher(s)

• Promoter: Baets Jonathan

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Next Generation Sequencing (NGS) technologies have resulted in the accumulation of a large amount of genetic causes for Mendelian diseases, with often no clear-cut link or evident cellular function correlating to the phenotype available. Conversely, a multitude of patients with Rare Diseases, of which many suffer from neuropathies, are lacking a genetic etiology. SPTAN1 (?-II-spectrin) provides an excellent example of this, with a notably high phenotypical heterogeneity but surprisingly little known about its molecular biology and cellular functions. Previously only associated with epilepsy and intellectual disability, we recently published novel mutations in SPTAN1 associated with Hereditary Motor Neuropathy (HMN). Furthermore, our own unpublished data show patients with ataxia and Hereditary Spastic Paraplegia (HSP), widening the phenotypical spectrum even further. I set out to uncover the molecular causes of the phenotypical heterogeneity present in SPTAN1, starting with the curation of an extensive database of SPTAN1 mutations and their associated phenotypes. Leveraging the information contained in this database through the use of machine learning techniques, I will perform experiments in carefully chosen patient-derived induced Pluripotent Stem Cells (iPSCs) that will allow the uncovering of differential effects between variants in SPTAN1 and their associated phenotypes, yield novel candidate genes for such disorders and teach us about the patho-biology of spectrins.

Researcher(s)

• Promoter: Baets Jonathan
• Co-promoter: Timmerman Vincent
• Fellow: Van de Vondel Liedewei

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Genetic causes of cerebral palsy Abstract Cerebral palsy (CP) is a clinical descriptive term that defines a heterogeneous group of non-progressive, neurodevelopmental disorders of motor impairment, which co-occur with a wide range of medical conditions such as epilepsy, autism, mental disorder, etc. It is the most frequent cause of motor impairment in children with an important impact on quality of life. It's prevalence ranges between 1.5 and 2.5 in 1000 live births. The causes of cerebral palsy are quite variable. Known causes are preterm birth, congenital (brain) abnormalities, intrauterine infection, thrombophilia etc. It was thought that asphyxia at birth was the most frequent cause of cerebral palsy. However, large population-based studies have shown that it is a causative factor in only 10% of CP patients. Recent studies demonstrate an important contribution of genetic factors in the etiology of CP. However, the genetic causes are heterogeneous and the mechanisms of action of these genes related to CP pathology are largely unknown. Genetic investigations in CP patients in Belgium were limited until recently. In this research project, we make a gene panel for CP that can be diagnostic in a cost-effective manner. Furthermore, we want to gain insight into the pathophysiology of CP and associated pathways, which can lead to better insight into the condition itself, early intervention and development of treatment and therapeutic interventions in the future. We performed diagnostic genetic studies in CP-patients that are followed at the Pediatric Neurology department of the University Hospital of Antwerp using (1) SNP-array to exclude chromosomal anomalies and (2) a whole exome sequencing (WES) based gene panel consisting of 200 genes associated with CP and CP-mimics. When no genetic diagnosis can be made in diagnostic setting, WES data are further studied in research setting. The found genetic variants are saved in a custom-made database that allows us to make genotype-phenotype correlations. This research strategy has led to the identification of de novo variants in the KIF1A gene in a relatively large proportion of our CP-population (6/100). These variants are localized in the KIF1A motor domain and can't be found in control databases. In silico prediction programs classify the variants as (probably) pathogenic. KIF1A is a kinesin motor protein, that is responsible for cargo transport along microtubule tracts. It is for example responsible for the transportation of ATG9, a key component in the autophagy pathway. It was demonstrated in C. Elegans that ATG9 regulates autophagy-induction at the synapse. We believe that pathogenic KIF1A-variants inhibit the induction of autophagy. The same mechanism has been described in the AP4-deficiency syndrome, one of the first identified genetic causes of cerebral palsy, caused by a mutation in a subunit of the AP4-complex. AP4 is involved in the transportation of ATG9A. Other mutations in autophagy genes have been described in association with neurological symptoms such as developmental delay, intellectual disability, spasticity, hypotonia, ataxia, epilepsy etc. The clinical characteristics seen in these gene mutations resemble those of CP. It is therefore thought that the presence of genetic variants that dysregulate autophagy, cause a reduced neuroprotective capacity against environmental factors such as hypoxic ischemia or inflammation. Because of this, an increased vulnerability for the development of cerebral palsy occurs. This hypothesis will be further investigated in our research project. Furthermore, we will analyze our population for new genetic variants that can cause cerebral palsy or cerebral palsy mimics. Key words Cerebral palsy, Single Nucleotide Polymorphism-array, Whole exome sequencing

Researcher(s)

• Promoter: Ceulemans Berten

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Radiation associated dysphagia (RAD) is one of the most serious and disabling complications in head and neck cancer survivors. Due to the specific nature of RAD, including the never-ending cascade of tissue fibrosis and muscle atrophy, treatment of RAD is very challenging and RAD often becomes chronic (C-RAD). Although the need for evidence-based and patient-supported therapy methods for C-RAD is loud and clear and internationally acknowledged, research addressing this issue is very scarce, heterogeneous and levels of evidence are low, retarding clinical implementation.. This multicentric project aims to fill in this need by conducting a 3-arms randomized controlled trial. The study design allows to investigate the effect of state-of-the-art and innovative rehabilitation methods in patients with C-RAD, comparing the efficacy and possible detraining effects of mere strengthening exercises (group 1) with a combination of strengthening exercises and functional swallowing therapy (group 2) and non-invasive brain stimulation added to that combination (group 3). In order to limit the additional burden for the patients, therapy sessions take place at home under supervision of a qualified speech language pathologist. Functional oral intake (i.e. what the patient really can eat) following 8 weeks of therapy is the primary outcome measure. Secondary outcome measures are related to changes in quality of life, muscle strength and swallowing function. Since clinical implementation of a therapy method requires that it is patient-supported, a dummy run will be conducted prior to actual data collection and patient-centred outcome parameters like adherence and patient attitudes and experiences are investigated. It is expected that the study results will facilitate and promote clinical implementation of evidence-based patient-centered care in this challenging population.

Researcher(s)

• Promoter: Van Nuffelen Gwen

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

The rising prevalence of eye diseases and our increasing life expectancy has accelerated the demand for ophthalmic therapeutics. While there is a clear market for novel ophthalmic medicines, these drugs must also be safe. There are two standard approaches to preclinical drug testing; 1) the in vitro approach where human cells or cell lines are tested in cultures on mostly plasticware, and 2) in vivo testing using healthy animals or animal models of disease. Neither of these approaches are ideal as both deviate significantly from the true human in vivo status and the native environment of the cells. Moreover, side effects can present in human subjects that did not occur in either in vitro or in vivo models which can have devastating effects to the patients. Organ-on-chip (OoC) technology is an emerging biomedical field that aims to provide a 3-dimensional dynamic tissue environment to more closely model human physiology. OoC emerged from computer technology disciplines and aims to reproduce the smallest functional unit possible to represent the chemical, mechanical and functional aspects of human organs. These "smallest functional units" are microfluidic cell culture chips where multiple human cell types can grow together and interact as tissue would. The potential of OoC in Ophthalmology, and in particular the cornea, has not yet been properly exploited. The cornea is of distinct pharmacological interest, as the majority of ocular medications are administered as an eyedrop. Current ophthalmological in vitro models are limited to just one or two layers of the cornea. In reality, the cornea is a highly complex 'organ' consisting of five layers, each of which has a very specific physiology, functional role and cellular pathways. There is an unmet need to create a complete in vitro cornea model with adequate complexity. OoC technology allows to create a true cornea-on-a-chip including every corneal layer, mimicking the natural state as close as possible from the anterior chamber all the way through to the epithelium at an air-liquid interface, just like the surface of our eyes. The transparency of the cornea results from the complex interplay between the cells and the surrounding supporting structures. When one of the layers is compromised, it directly affects the integrity of the corneal system, possibly resulting in cellular damage or death which in turn directly impacts vision. Each layer of the cornea plays a role in the drug absorption process. The epithelial layer of the cornea is lipoidal in nature and acts as the first tissue barrier to drug absorption. On the other hand, the stroma is hydrophilic in nature and comprises 90% of the corneal thickness. Endothelium is the innermost layer separating barrier between the stroma and aqueous humour. This layer helps to maintain the corneal transparency due to its pump-and-leak mechanism that keeps the stroma in a relatively dehydrated state. In addition to difficulties related to the absorption of the drugs, metabolization through corneal enzymes also reduces drug bioavailability. The joined action of the three corneal layers maintains homeostasis and thus transparency. The drugs applied to treat eye-related conditions as well as those applied post-operatively (hypotensive drops, antibiotics, mydriatics and anti-inflammatory drugs) are applied topically and have to travel through the cornea where they could cause off-target damage. Therefore, the cornea model envisioned in this project includes the three main corneal layers: epithelium, stroma and endothelium. This is markedly different to existing in vitro models where mostly only the epithelium and in very few cases a part of the stroma is included. The aim of the project is to deliver a proof-of-concept for the design, production and validation of a cornea-on-chip model of the complete human cornea including all cell layers, that recreates the physiological environment precisely to adequately mimic the native human cornea.

Researcher(s)

• Promoter: Koppen Carina
• Fellow: Van Meenen Joris

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Hearing loss has a significant impact on quality of life and society in general. Hearing impairment is the most frequent sensory deficit in human populations, affecting 360 million people worldwide. It was listed by the World Health Organization as one of the priority diseases for research into therapeutic interventions to address public health needs. DFNA9 is a dominant hereditary disorder, caused by heterozygote mutations in the COCH gene, which progressively leads to bilateral deafness and balance loss by the age of 50-70 years. Currently, no treatment is available to prevent hearing loss or balance loss in DFNA9 patients. Local gene therapy to restore hearing or prevent hearing loss has been studied in neonatal mouse models for several years. Currently, a clinical study is ongoing in adult patients with profound hearing loss to restore hair cells by injecting virus-based vectors -carrying correcting genetic information- directly into the inner ear. In this project, we aim to generate an inner ear gene therapy tool to prevent hearing loss in a pre-clinical mouse model of DNFA9.

Researcher(s)

• Promoter: Van Rompaey Vincent

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Hearing impairment is the most frequent sensory deficit in the human population, affecting 440 million people worldwide, whereby loss of hearing and balance has a significant impact on quality of life and society. Hearing loss is also listed by the World Health Organization as a priority disease for research into therapeutic interventions to address public health needs. DFNA9 (DeaFNess Autosomal 9) is an autosomal dominant hearing disorder caused by a heterozygous gain-of-function mutation in the COCH gene (Coagulation Factor C Homology) and is characterized by progressive late-onset (3rd-5th decade) sensorineural hearing loss (SNHL) and deafness. At current, it is believed that the presence of aberrant COCH proteins in the extracellular matrix (ECM) of the inner ear leads to local cell damage resulting in progressive hearing loss. Within Belgium and the Netherlands, there are > 1000 patients affected by the P51S COCH mutation, who – in the current absence of a disease modifying therapy – will develop deafness and balance loss. Furthermore, there are over twenty different COCH mutations identified in people from all over the world that lead to SNHL. Given the genetic nature of this disorder with highly specific mutations, as well as recent advances in CRISPR-nuclease mediated gene therapeutic approaches, there is a great opportunity to develop a successful therapeutic strategy to reduce or prevent DFNA9-induced SNHL.

Researcher(s)

• Promoter: Van Rompaey Vincent
• Co-promoter: Ponsaerts Peter
• Co-promoter: Van Camp Guy

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

The corneal endothelium covers the inner surface of the cornea, the transparent window of the eye. When this cell layer gets damaged, this leads to painful blindness, necessitating transplantation. Currently, transplantation is limited by a severe donor shortage. That is why researchers aim to fabricate a lab grown tissue to treat blind patients and shorten waiting lists. However, my PhD project aims to develop an innovative membrane with the aim to eventually exploit in vivo regeneration without transplantation of cells. More specifically, this project includes the in vitro development of a membrane that is covered with miniscule patterns, which have 2 functions. On the one hand, the shape of the pattern itself will act as one-way signals that guide corneal endothelial cells to the middle of the cornea to restore its original barrier function. On the other hand, the patterns contain drugs that are specifically released when cells overgrow the patterns, thereby accelerating the process even further. I have 2 different strategies for its content, namely filling these patterns with either growth factors or exosomes secreted by stem cells. Eventually, I will establish a proof-of-principle in rabbits to prove the efficiency. Advantages are that this is a potential cost-effective off-the-shelf product that is safer for the patient as it does not involve any cells compared to cell therapy or transplantation and that the applicability stretches beyond the field of ophthalmology.

Researcher(s)

• Promoter: Koppen Carina
• Co-promoter: Ni Dhubhghaill Sorcha
• Fellow: Vercammen Hendrik

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Aside from typical symptoms such as postural imbalance, vertigo, dizziness, nausea, and problems with gaze stabilization, patients with vestibular disorders (VD) often suffer from cognitive impairment (memory loss, loss of concentration, inability to multitask, fatigue, and headaches). On the one hand, these cognitive symptoms may be directly related to altered (e.g. hippocampal) vestibular projections throughout the brain, which are also involved in cognitive functions. On the other hand, these symptoms may be indirectly explained by difficulties in performing a motor and cognitive task simultaneously (dual-tasking), expressed by impaired cognitive-motor interference. The aim of the current study is to elucidate the impact of VD on cognitive and motor function, assessed in single and dual-task (DT) condition. Therefore, a test battery was developed and constructed based on a systematic review on psychometric properties of DTs in a variety of populations. The test protocol comprises five different cognitive tests, all assessing a different cognitive domain, which will be performed separately (single task) as well as during motor tasks (DT). This test protocol will be standardized in healthy controls, and subsequently validated in patients with bilateral vestibulopathy. The standardized and validated test protocol will then be performed in persons with unilateral vestibular loss. Finally, possible correlations between functional data and neuroimaging will be explored.

Researcher(s)

• Promoter: Van Rompaey Vincent

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Obstructive sleep apnea (OSA) is a prevalent public health issue with an attributable risk of cardio- and cerebrovascular morbidity and mortality. Furthermore, OSA is related to a high socioeconomic burden due to its clinical daytime consequences such as excessive daytime sleepiness, impaired cognitive performance and reduced quality of life. Oral appliances that protrude the mandible, the mandibular advancement devices (MAD), significantly reduce OSA severity in the majority of patients. However, in a third of patients, the efficacy is not medically appropriate to reduce the long-term consequences of OSA. Furthermore, the efficacy of MAD therapy is inconsistent among patients. Therefore, a high need exists for upfront prediction of treatment outcome in the individual OSA patient. There is no validated method that can achieve upfront selection of candidates for MAD therapy in an accurate and reliable way. Nowadays, it is increasingly recognized that OSA is a multifactorial disease. In the proposed research project, a prospective prediction model with a combination of different pathophysiological traits will be assessed. Furthermore, up to now, our understanding of MAD therapy relies on relatively small studies lacking power. Therefore, we will evaluate this predictive model, as well as the long-term effectiveness, morbidity and mortality in a large international cohort of patients treated with MAD.

Researcher(s)

• Promoter: Vanderveken Olivier
• Co-promoter: Braem Marc
• Co-promoter: Verbraecken Johan
• Fellow: Dieltjens Marijke

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

The human eye is a unique, biological complex but vulnerable entity. It lacks protection of keratinized epithelium against infection and desiccation, as seen in almost every other area of the body. However, the ocular surface is specialised to protect the ocular structures and respond rapidly upon injury, while maintaining a smooth refractive surface to ensure visual acuity. One of the specialised cellular layers contributing to ocular tissue homeostasis is the conjunctiva. This thin mucous membrane belongs to the ocular surface epithelia, covering the sclera and the inside of the eyelids. In some ocular disorders, the conjunctiva is damaged, resulting in extensive scarring and inflammation, which can lead to several pathological conditions such as eyelid distortions, tear film disruptions, severe dry eyes, corneal ulcers and eventually blindness. The management of severe conjunctival surface disorders remains challenging for ophthalmologists worldwide. The conventional treatment comprises the surgical excision of the diseased conjunctiva. Normal wound healing post resection is based on epithelial migration from adjacent healthy conjunctiva to the wounded area. However, this healing process cannot take place in patients lacking sufficient healthy residual conjunctiva. Here, fibrosis and scar formation will occur, often reintroducing several pathological conditions as described above. Hence to avoid sequelae, the ocular surface requires reconstruction post excision using a cellularized conjunctival substitute. In this project, we aim to meet this unmet medical need by creating a cellularized conjunctival substitute for reconstructive surgery. By introducing fully synthetic self-assembling collagen-like-peptide hydrogels as carrier for human conjunctival-derived cells and eliminating all animal-derived components, we aim to provide a safe, consistent and functional conjunctival replacement. The graft's functionality will be tested in vitro by means of specifically designed tests for presence of conjunctival epithelial cells (barrier formation against infectious microbes), mucin-producing goblet cells (tear film stabilization) and stem cells (epithelium renewal).

Researcher(s)

• Promoter: Koppen Carina
• Fellow: Van Acker Sara

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Eye diseases are responsible for a huge economical burden globally, but are also associated with a drastic decrease in quality of life. Some of these diseases are associated to the loss of transparency of the window of the eye, namely the cornea. The cornea is the outermost part of the eye and is composed out of 3 different cell layers. The innermost layer, the corneal endothelium, maintains critical corneal hydration. Upon ageing, disease or trauma, this cell layer can be damaged to such an extent that the cornea swells and loses its transparency, which leads to blindness. Currently, the only treatment consists of full or partial transplantation of a donor cornea. Unfortunately, the supply does not meet the demand by far since only 1 donor is available per 70 patients. To overcome this limitation, the present project aims to develop a synthetic alternative that allows the efficient transplantation of healthy cells towards the site of tissue defect. To this end, biodegradable membranes will be developed using a combination of smart polyesters with shape memory effects, in combination with gelatin derivatives that mimic the cellular environment. These carriers will be seeded with cells, to allow transplantation to the site of tissue defect. Furthermore, the membranes will be analysed in depth both for mechanical properties as in vitro behavior prior to in vivo animal studies. Ideally, at the end of the project, the developed membrane should be ready for clinical trials.

Researcher(s)

• Promoter: Koppen Carina

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

The world population has been aging dramatically, with 12% aged 60 years or older, and a rising number developing dementia. Yet, until now no cure or therapy to slow down the disease has been identified. Recent studies have established that hearing loss increases the risk for developing dementia. Because hearing loss can be treated with a hearing aid or cochlear implantation, this could potentially delay the onset of dementia. Many studies have reported improvement in cognition after hearing rehabilitation, but this might have been caused by just hearing the mostly verbal tests better. Many studies have demonstrated that balance organ function, located in the inner ear, also has an effect on cognition. However, while hearing loss and balance organ function loss often occur simultaneously, it has not been systematically evaluated in older adults. Our aim is to study the effect of hearing loss and balance organ function loss on learning and memory (i.e. cognition) in older subjects (55 years or older) and patients with mild cognitive impairment and Alzheimer's disease. We will do so by systematically evaluating hearing and vestibular function in these subjects, by using a cognitive assessment tool that is adapted to a potentially hearing impaired population, by using objective measurements of electrical activity in the auditory cortex evoked by sound and by analyzing MRI volume changes in relevant areas of the brain to detect who is at risk for developing cognitive impairment.

Researcher(s)

• Promoter: Van Rompaey Vincent
• Co-promoter: Cras Patrick
• Co-promoter: Mertens Griet
• Co-promoter: Van Ombergen Angelique

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Sporadic Inclusion-Body Myositis (sIBM) is the most common myopathy in older adults and has a significant impact on the quality of life; no treatment exists to date. Histopathologically sIBM is characterized by degenerative as well as inflammatory features. In addition to this evident inflammation, striking similarities are observed between sIBM and neurodegenerative diseases. Alternative disease mechanism are suspected since sIBM has no classic genetic cause nor does it respond to immunosuppression as a "classic" inflammatory disorder would. Previously we have taken advantage of the availability of disease tissue due to diagnostic muscle biopsies. This allows 'proteomics' studies that capture the entire set of proteins in the diseased muscle and the key 'signatures' of the underlying mechanisms. A total of 61 muscle samples of sIBM-patients and controls were studied. Integrative data-analysis points towards three crucial disease pathways. These are involved in cell growth and repair, DNA damage response and inflammation-control. In the current project we will further study the role of these pathways by performing focused protein expression studies in muscle tissue and through the specific manipulation of these pathways in human-derived myoblast cell-lines in order to reproduce both sIBM pathology and proteomesignature. This novel cell system can be used as a disease model and will aid in the design of disease 'biomarkers' and therapies for sIBM.

Researcher(s)

• Promoter: Baets Jonathan

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Hearing loss has a significant impact on quality of life and society in general. Hearing impairment is the most frequent sensory deficit in human populations, affecting 360 million people worldwide. It was listed by the World Health Organization as one of the priority diseases for research into therapeutic interventions to address public health needs. DFNA9 is a dominant hereditary disorder, caused by heterozygote mutations in the COCH gene, which progressively leads to bilateral deafness and balance loss by the age of 50-70 years. Currently, no treatment is available to prevent hearing loss or balance loss in DFNA9 patients. Local gene therapy to restore hearing or prevent hearing loss has been studied in neonatal mouse models for several years. Currently, a clinical study is ongoing in adult patients with profound hearing loss to restore hair cells by injecting virus-based vectors -carrying correcting genetic information- directly into the inner ear. In this project, we aim to generate an inner ear gene therapy tool to prevent hearing loss in a pre-clinical mouse model of DNFA9. Using Adeno-associated virus (AAV)-based vectors, we will apply CRISPR-Cpf1 genome engineering technology to target directly within in the cochlea Coch genomic DNA in a safe and effective way in order to disrupt expression of the mutant (and wild type) Coch protein before onset of disease. Hereby, we expect to reduce or prevent DNFA9-associated sensorineural hearing loss.

Researcher(s)

• Promoter: Van Rompaey Vincent
• Co-promoter: Ponsaerts Peter
• Fellow: Verdoodt Dorien

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

The current project proposes a randomized, placebo-controlled study comparing the effects of high-definition transcranial direct current stimulation (HD-tDCS) to a control (sham) group. HDtDCS neuromodulation is, in general, considered as a save intervention as it is a form of noninvasive brain modulation with no to relatively mild side effects. Up until now, a total of 31 studies evaluated the effects of tDCS on tinnitus reporting a variety of effects ranging from no effects to significant tinnitus reduction. The present protocol proposes a randomized controlled trial comparing the effects of HD-tDCS therapy taking into account confounding factors such as age, gender, anxiety, depression and hearing loss (which are often not considered in previous studies). In this context, the proposed clinical trial will be the first high-quality powered randomized controlled trial of its kind and the results would be much appreciated by the tinnitus community as stated by the TINNET work group (a European network for tinnitus research and management). In addition, cognitive aspects such as attention and memory will be evaluated by use of a cognitive test battery. It has been previously shown that tinnitus might have deteriorating effects on cognition but the outcomes remain speculative so far. As such, a thorough cognitive exam will be carried out as well as the measurement of cortical auditory evoked potentials (CAEPs). CAEPs are the neurophysiological correlate of auditory processing in the brain which can be measured. This provides a measure that can be taken into account in the study providing an objective evaluation of tinnitus burden and tinnitus alleviation before and after tinnitus therapy. In addition, these measurements can be linked to the cognitive performance of patients which has never been done before.

Researcher(s)

• Promoter: Van Rompaey Vincent
• Co-promoter: Van de Heyning Paul

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

DNFA9 is a cause of autosomal dominant (AD) non-syndromic late-onset sensorineural hearing loss (SNHL) associated with progressive bilateral vestibular failure (BVF). The age of SNHL onset varies depending on the mutation though the average onset age lies around 3rd-5th decade. It typically starts as downsloping of the audiogram at the age of onset and evolution towards deafness. DFNA9 is caused by mutations in the COCH gene (Coagulation Factor C Homology), which is located on chromosome 14q12-13 and encodes for a 550 amino acid protein, cochlin, which is expressed throughout the inner ear in spindle-shaped cells located along nerve fibers between the spiral ganglion and sensory epithelium. Over twenty mutations have been identified in regions, including North America, Japan, Australia, Korea, China and Belgium/Netherlands. Our objective is to establish an in vitro proof-of-principle for a gene therapeutic approach that targets mutant cochlin expression in the inner ear using Anc80L65AAV/CRISPR/Cas9-mediated gene editing. We hope to establish in vitro that this technique enables specific correction or downregulation of the mutant COCH gene in mammalian cell lines without modulating the normal COCH allele, which is still present in this heterozygous disorder. This work can provide proof-of-concept for in vivo studies in transgenic heterozygous COCH mice targeting the mutated COCH gene by means of an AAV.

Researcher(s)

• Promoter: Van Rompaey Vincent
• Co-promoter: Ponsaerts Peter
• Co-promoter: Van Camp Guy
• Co-promoter: Van de Heyning Paul

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Obstructive sleep apnea (OSA) is a chronic disease that is caused by partial or complete upper airway collapse during sleep. OSA is a highly prevalent disorder linked to a range of considerable health risks. Application of continuous positive airway pressure (CPAP) is regarded as the gold standard treatment for more severe OSA. The clinical effectiveness of CPAP is often hampered by the inadequate adherence to CPAP mainly due to limited tolerance of the treatment. The techniques that are currently used for the selection of OSA patients for alternative, non-CPAP treatment options such as oral appliance therapy, with mandibular advancement device (MAD), or upper airway stimulation (UAS) synchronized with ventilation, are rather invasive. An integrated, innovative approach that might allow for non-invasive assessment of the anatomical traits of the individual upper airway will be evaluated. The hypothesis of this research project is that these anatomical traits, site of upper airway collapse and degree of pharyngeal collapsibility, can be derived from the respiratory flow signal that is measured during each routine sleep study anyway. The predictive value of this innovative and non-invasive method will be analyzed, also in comparison to the techniques that are currently employed for this purpose of patients' selection. Whether the innovative and non-invasive approach has a better predictive value towards a successful treatment outcome with UAS with or without MAD will be investigated. The main goal is to improve the results with these treatment options for OSA based on the non-invasive assessment of the anatomical traits of the upper airway in the individual OSA patient.

Researcher(s)

• Promoter: Vanderveken Olivier
• Co-promoter: Braem Marc
• Co-promoter: Van de Heyning Paul
• Fellow: Kazemeini Elahe

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

English Title: Tissue engineering for conjunctival reconstruction: Introducing self-assembled collagen-like-peptide scaffolds for the expansion of human conjunctival-derived cells in a xeno-free and serum-free environment. The human eye is a unique, biological complex but vulnerable entity. It lacks protection of keratinized epithelium against infection and desiccation, as seen in almost every other area of the body. However, the ocular surface is specialised to protect the ocular structures and respond rapidly upon injury, while maintaining a smooth refractive surface to ensure visual acuity. One of the specialised cellular layers contributing to ocular tissue homeostasis is the conjunctiva. This thin mucous membrane belongs to the ocular surface epithelia, covering the sclera and the inside of the eyelids. In some ocular disorders, the conjunctiva is damaged, resulting in extensive scarring and inflammation, which can lead to several pathological conditions such as eyelid distortions, tear film disruptions, severe dry eyes, corneal ulcers and eventually blindness. The management of severe conjunctival surface disorders remains challenging for ophthalmologists worldwide. The conventional treatment comprises the surgical excision of the diseased conjunctiva. Normal wound healing post resection is based on epithelial migration from adjacent healthy conjunctiva to the wounded area. However, this healing process cannot take place in patients lacking sufficient healthy residual conjunctiva. Here, fibrosis and scar formation will occur, often reintroducing several pathological conditions as described above. Hence to avoid sequelae, the ocular surface requires reconstruction post excision using a cellularized conjunctival substitute. In this project, we aim to meet this unmet medical need by creating a cellularized conjunctival substitute for reconstructive surgery. By introducing fully synthetic self-assembling collagen-like-peptide hydrogels as carrier for human conjunctival-derived cells and eliminating all animal-derived components, we aim to provide a safe, consistent and functional conjunctival replacement. The graft's functionality will be tested in vitro by means of specifically designed tests for presence of conjunctival epithelial cells (barrier formation against infectious microbes), mucin-producing goblet cells (tear film stabilization) and stem cells (epithelium renewal).

Researcher(s)

• Promoter: Koppen Carina
• Co-promoter: Tassignon Marie-Jose
• Fellow: Van Acker Sara

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Swallowing disorders are considered to be the most important long term adverse event after radiotherapy for head and neck cancer (HNC), impacting on health related quality of life (QoL). An increasing number of studies showed a significant positive effect of prophylactic swallowing exercises (PSE) on swallowing function in HNC-patients treated with (chemo)radiotherapy. Low adherence rates are however a major issue, preventing clinical implementation of PSE. This multicenter randomized trial investigates the effect service-delivery model (home practice versus app-supported versus therapist supported) on actual patient compliance, swallowing function and QoL. Secondly, the effects of multiple covariates patients and disease characteristics and patients attitudes towards exercising are investigated. The final part involves a cost-effectiveness study.

Researcher(s)

• Promoter: Van Nuffelen Gwen

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Head and neck cancer is a distressing cancer with a great impact on quality of life. Recently, the amount of oropharyngeal cancers in patients younger than 50 years increases significantly due to the human papillomavirus. Chemo-radiotherapy results in a higher patient survival, but up to 59% of these patients experience swallowing problems during or after the treatment, called radiationassociated dysphagia (RAD). RAD has a high impact on quality of life and the medical consequences are life threatening and immensely demanding on health care resources. The tongue plays an important role during swallowing, so an important underlying mechanism of RAD in these patient group is reduced tongue strength. But few is known about the pathophysiology behind the RAD and the exact link with tongue strength. Recently, multiple studies have shown that strengthening exercises can have a positive effect on tongue strength, swallowing function, and quality of life in healthy adults and various patient populations. But evidence in this specific population is rather scarce and there is no consensus on the content of an effective therapy regimen. A thorough study of the swallowing function, tongue strength, quality of life and other related factors will create insight in risk factors for developing RAD. This study aims to deliver the essential scientific support needed to implement new insights and recently developed techniques for swallowing rehabilitation based on tongue strength training.

Researcher(s)

• Promoter: De Bodt Marc
• Fellow: Van den Steen Leen

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Sacral neuromodulation is a minimally invasive treatment for several pelvic organ dysfunctions. currently intention to treat results vary between 50-60%. Reasons for the low success rate might be suboptimal patient selection or suboptimal lead placement. This project aims to identify factors related to lead placement that might influence outcome of treatment.

Researcher(s)

• Promoter: De Wachter Stefan

Research team(s)

• Translational Neurosciences (TNW)
• Antwerp Surgical Training, Anatomy and Research Centre (ASTARC)

Project type(s)

• Research Project

Abstract

Obstructive sleep apnea (OSA) is a common disorder associated with considerable health risks including mortality. The recommended treatment option for more severe OSA is continuous positive airway pressure or CPAP. It has been demonstrated that CPAP is able to mitigate the OSA-associated risks but its effectiveness remains rather low as its use is often hampered by poor tolerance. Consequently there is a high need for non-CPAP therapies. The challenge with these therapies is that the outcome in unselected patients is variable. In this project we will focus on an innovative approach that would allow to determine all pathophysiological traits in the individual OSA patient. First we aim at demonstrating that the anatomical traits, site of upper airway obstruction and tendency of the upper airway to collapse during sleep, can be derived from flow signals that are collected during sleep studies anyway. Secondly we will conduct studies to predict the outcome with non-CPAP therapies integrating the noninvasive anatomical assessment with the validated method for phenotyping. Two distinct types of surgery will thus be analyzed. Lastly we will apply the method for determining the traits of patients that undergo a combination treatment. This project aims at identifying predictors of treatment success in the individual patient based on a better understanding of OSA pathophysiology. This individualized therapy selection will likely yield to better health outcomes with non-CPAP therapies.

Researcher(s)

• Promoter: Van de Heyning Paul
• Fellow: Vanderveken Olivier

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Inherited Peripheral Neuropathies (IPN) constitute a large and diverse group of disorders causing length-dependent neurodegeneration of axons in the peripheral nervous system (PNS). As many other neuromuscular disorders, IPN are chronic, debilitating and in some instances life-threatening conditions resulting in tremendous disease burden for patients and society. Affecting 1 in 2500 individuals, IPN share the challenges common to other 'rare disorders' namely substantial delays in diagnosis due to lack of reliable diagnostic tools; lack of specialized centres and standards for optimal patient care; lack of fundamental understanding of the mechanisms of disease and the absence of effective therapies. For three types of IPN (pure motor forms, pure sensory forms and congenital forms) the 'missing heritability' is as high as 70%. In this project we will start from biobanking of patients with the above-mentioned understudied types of IPN and we will systematically map out the phenotypic characteristics. In parallel, we will conduct large-scale genetic studies using next-generation sequencing techniques in these cohorts. By doing so we will tackle the existing knowledge gap in the genetic groundwork of PNS disease. This will evidently improve patient diagnosis but will at the same time significantly enlarge our understanding of the crucial mechanisms leading to axonal degeneration of the peripheral nervous system. Thirdly we aim to study the striking variability in disease severity of IPN through detailed genotype-phenotype correlation. Ultimately this will facilitate future studies designing reliable 'disease biomarkers' amenable for disease severity assessment on the one hand and the identification of novel targets for future therapeutic strategies on the other hand.

Researcher(s)

• Promoter: Baets Jonathan
• Fellow: Beijer Danique

Research team(s)

• Neurogenetics Group
• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

The overall aim of this project is to develop a scaffold with collagen nanofibre alignment to replace the existing use of human amniotic membranes for ocular surface reconstruction. The expected outcome is a standardized prototype composite graft with improved transparency, mechanical strength, bio-integration and reduced microbial susceptibility, realised through combining biomaterials engineering, protein surface modification and stem cell technologies. During the course of this research we intend to bring this prototype to a proof-of-concept in a rabbit model of limbal stem cell deficiency. This cutting-edge research will lay the groundwork for the development of sustainable biomimetic artificial corneas through an extension of its engineering.

Researcher(s)

• Promoter: Tassignon Marie-Jose
• Co-promoter: Zakaria Nadia
• Fellow: Haagdorens Michel

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

The conjunctiva is a thin membrane, which covers the white part of the eye and the inside of the eyelids. It is essential that this membrane functions correctly as it plays an important role in the maintenance of a healthy ocular surface and the preservation of vision. In some ocular disorders, the conjunctiva is damaged resulting in excessive scarring leading to surface disorders such as severe dry eyes, eyelid distortions and even blindness. Current treatment strategies for conjunctival reconstruction include surgically removing the diseased tissue and placing a human amniotic membrane over the bare sclera to aid in tissue regeneration. However, at times, either due to the nature of the diseased environment or a lack of properly functioning conjunctival epithelial stem cells, there is aberrant wound healing with scar formation, worsening the outlook for ocular reconstruction. In this project, we address this issue by creating a cellularized conjunctival substitute that can be transplanted onto the ocular surface after debridement of diseased tissue. This substitute is expected to reduce/eliminate scar formation and facilitate regeneration by providing a functional conjunctival replacement, containing both mucin-producing goblet cells to stabilize the tear film as well as conjunctival epithelium to establish a barrier to infectious microbes. The human amniotic membrane will be investigated as a biological scaffold for cultivating the cellular grafts for this purpose.

Researcher(s)

• Promoter: Tassignon Marie-Jose
• Co-promoter: Zakaria Nadia
• Fellow: Van Acker Sara

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

In this project an innovative approach to the diagnosis of pain in ICU patients will be developed. On the basis of this objective measurement of pain, a mechnism-based treatment for individual patients will be studied.

Researcher(s)

• Promoter: Hans Guy

Research team(s)

• Translational Neurosciences (TNW)

Project website

Project type(s)

• Research Project

Abstract

Epilepsy is a neurological disorder affecting about 60 million people worldwide. It is charactised by recurrent unprovoked seizures. Mesial temporal lobe epilepsy (MTLE), the most common form of focal epilepsies, is not controlled by current anti-epileptic treatements in around 1/3rd of the patients. An epileptogenic insult leads to a strong inflammatory response characterized by activation of innate brain immune cells as well as migration of immune cells from the peripheral blood due to a compromised blood-brain barrier. These events could induce epileptogenesis by affecting neurodegeneration, reorganization of neuronal circuits, neurogenesis as well as directly promoting the neuronal excitability. An inflammatory response consists of an initial acute classical activation (M1) of the immune cells that leads to release of pro-inflammatory cytokines that may promote disease progression. This is followed by an M2 alternate activation that releases anti-inflammatory cytokines such as IL-13 that initiates repair mechanisms. The goal of this project is to inhibit the epileptogenesis following an initial brain insult by altering the M1/M2 balance of the brain inflammation towards the protective M2 phase. We hypothesize that promoting the M2 activation of immune cells would inhibit development of epileptic seizures in animal models. In this proposal, we aim to administer genetically modified IL-13 expressing M2a polarized macrophages in the mouse brain, at day 2, after the induction of kainic acid induced status epilepticus, a commonly used model of MTLE. We also aim to utilize the seizure-induced leakage in the blood-brain barrier for the transmigration of modified M2 macrophages into the brain following systemic administration. We expect to observe a protective effect of this treatment on neuroinflammation and other neuropathological processes induced by the status epilepticus. More funding will be applied for with an aim to test whether modulating the M1/M2 polarization of brain inflammation during epileptogenesis would alter the development of epileptic seizures in this mouse model. This project could provide novel approaches for the treatment and prevention of epilepsy as well as evaluate the possibility of utilizing systemically delivered macrophages for delivery of therapeutic agents into the epileptic brain.

Researcher(s)

• Promoter: Ali Idrish

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Human corneal endothelial cells (HCEnC) regulate fluid and solute transport across the posterior surface of the human cornea and actively maintain the cornea in a dehydrated state, which is crucial for optical transparency.The dual function of the corneal endothelium is described as the "pump-leak hypothesis" which is essential to allow nutrition to the cornea whilst maintaining its avascularity and transparency. There is no evidence that human endothelial cells divide under normal circumstances as they are arrested in G1 phase of the cell cycle, although they can be induced to divide in vitro. When the amount of corneal endothelial cells decreases below a certain threshold, this cell layer can no longer pump sufficient fluid back to the anterior chamber, resulting in an irreversibly swollen, cloudy cornea. Despite its success, corneal transplantation (either full-thickness or partial) is limited worldwide by the shortage of suitable donor corneas incurring long waiting times. Initial progress to overcome this global shortage is the use of one donor cornea for multiple partial keratoplasties ("split-cornea transplantations"), by using one donor cornea for a partial endothelial and a stromal transplantation. This project aims to investigate ex vivo expansion of corneal endothelial cells to develop a cell sheet based therapy. This would overcome donor deficit that limits the treatment of corneal endotheliopathies. The principle is to expand primary human corneal endothelial cells isolated from human cadavers and to seed them on an ideal scaffolding material to introduce these cells in the patient. Specifically in this project we propose the expansion of human corneal endothelial cells (HCEnC) on human lens capsules to obtain a composite graft. The final goal of this project is a proof-of-principle of this functional cell sheet in a rabbit corneal endotheliopathy model.

Researcher(s)

• Promoter: Koppen Carina
• Promoter: Tassignon Marie-Jose
• Co-promoter: Zakaria Nadia
• Fellow: Van den Bogerd Bert

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

The aim of the project is to i) set-up chronic animal models for different neurological diseases, ii) to establish specific, but also common biomarkers for these diseases using in vivo imaging modalities (focusing on small animal PET imaging) and validation with histological techniques, iii) follow-up disease progress using these in vivo biomarkers in conjunction with bio-imaging, and iv) to evaluate treatment response using these in vivo biomarkers with bio-imaging.

Researcher(s)

• Promoter: Dedeurwaerdere Stefanie
• Fellow: Dedeurwaerdere Stefanie

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Obstructive sleep apnea (OSA) is a prevalent public health issue and strong and independent risk factor for cardio- and cerebrovascular diseases. Therefore, adequate treatment is important. Continuous positive airway pressure (CPAP) is considered the gold standard non-invasive treatment modality, although oral appliances that protrude the mandible are increasingly prescribed. Both non-invasive treatment modalities are symptomatic treatments and therefore lifelong device therapies, so the patient's compliance is of primary importance since it is only effective when appropriately used. The therapeutic effectiveness of both therapies is given by the product of efficacy with objective compliance. For both CPAP and oral appliance therapies, it is important to determine the therapeutic effectiveness in the optimal 'dose', being pressure for CPAP and mandibular protrusion for oral appliances. However, in the absence of a gold standard protocol to find the optimal mandibular protrusion for oral appliance therapy, the titration procedure remains 'trial and error'. Therefore, in the proposed research project, the feasibility of a titration procedure during polysomnography will be assessed and compared with a titration procedure under direct visualization of upper airway collapse during drug-induced sedation endoscopy, for both therapies. Furthermore, the pathophysiologic and cardiovascular alterations during both treatment modalities in the established optimal dose will be studied.

Researcher(s)

• Promoter: Van de Heyning Paul
• Co-promoter: Braem Marc
• Co-promoter: Vanderveken Olivier
• Fellow: Dieltjens Marijke

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Epilepsy is a devastating disorder affecting 65 million people worldwide characterized by recurrent seizures. This research project will investigate a novel hypothesis connecting translocator protein (TSPO) overexpression, a hallmark of brain inflammation, and spontaneous seizure outcome during the development of epilepsy (epileptogenesis). Our hypothesis is supported by the observation that i) TSPO is highly up-regulated in epilepsy and ii) our preliminary data suggest a relationship between TSPO overexpression and spontaneous seizure outcome. Unraveling this relationship will enable us to assess TSPO as a biomarker for maladaptive neuroplasticity during epileptogenesis. Firstly, by means of translational techniques, we will investigate longitudinally the pattern of TSPO expression during epileptogenesis in vivo in the kainic acid-induced status epilepticus (KASE) model. Secondly, the role of TSPO in epileptogenesis will be investigated by the study of the effects of the absence of TSPO in the TSPO knockout mouse, and by pharmacological stimulation of TSPO in the KASE model. This innovative project will increase our understanding of brain excitability during epileptogenesis offering a biomarker to identify patients at risk and moving the field forward giving a contribution to the development of therapies to prevent acquired epilepsy.

Researcher(s)

• Promoter: Dedeurwaerdere Stefanie
• Promoter: Verhaeghe Jeroen
• Co-promoter: Dedeurwaerdere Stefanie
• Co-promoter: Verhaeghe Jeroen
• Fellow: Bertoglio Daniele

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

We propose a novel hypothesis for the development of PTE with a central role for ECM modulating components MMP-9 and uPA. TBI results in blood-brain barrier disruption, hyperexcitability and primary damage triggering repair mechanisms such as modulation of the ECM by proteases MMP-9 and uPA. These alterations in ECM proteases MMP-9 and uPA, followed by brain inflammation, induce abnormal synaptic remodeling and epileptogenesis, ultimately leading to PTE.

Researcher(s)

• Promoter: Dedeurwaerdere Stefanie
• Promoter: Verhoye Marleen
• Co-promoter: Dedeurwaerdere Stefanie
• Co-promoter: Staelens Steven
• Fellow: Missault Stephan

Research team(s)

• Translational Neurosciences (TNW)
• Bio-Imaging lab

Project type(s)

• Research Project

Abstract

This is a fundamental research project financed by the Research Foundation – Flanders (FWO). The project was subsidized after selection by the FWO-expert panel.The human cornea is transparent and depends on this property to allow vision. Damage to the stem cell population that maintains the cornea surface results in Limbal Epithelial Stem Cells Deficiency (LSCD). This results in conjunctival overgrowth of the cornea with stromal scarring, corneal neovascularisation and opacification with decreased visual acuity, pain and photophobia. Current surgical treatment for LSCD includes transplanting large segments of donor excised limbal tissue but has a high risk of complications. Recent research has shown the benefit and feasibility of small limbal grafts cultured on biologically-derived scaffolds, e.g. human amniotic membranes. However, these are optically translucent at best. Being biologically derived they are difficult to standardise and carry potential health risks. Our objective, therefore, is to take a multidisciplinary approach to develop a synthetic alternative with superior cell-interactive properties that circumvents the problems with current limbal stem cell delivery scaffolds. Our research strategy is to exploit the recent introduction of human recombinant collagen that displays nano-fibre alignment under shear deposition to develop transparent, mechanically stable nano-implants that mimic the corneal collagen alignment seen in normal, healthy corneas. In order to further enhance cellular attachment, improved delivery and biointegration, the scaffolds will be enhanced through nano-printing of surface peptides. Collectively we will bring this nano-corneal scaffold to a proof-of-principle in animal models of limbal stem cell deficiency. By providing advancements in corneal regeneration we will be able to gain more insight into regenerative medicine as a whole. The data that we will acquire from this research will help us better understand the role that collagen nano-fibre alignment and surface nano-patterning plays in improving implant integration, and survival eventually paving the way to full thickness synthetic corneal replacements in the future. Our expected results include new scaffolds for delivery of stem cells that will have an impact of healthcare, in particular ophthalmology. However, the technologies developed also form a broader nanotechnology base that can be extended to regeneration of other target organs. An IP protection and dissemination strategy will ensure our economic and scientific impacts.

Researcher(s)

• Promoter: Tassignon Marie-Jose
• Co-promoter: Zakaria Nadia

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

This project brings together considerable expertise from academic and industry partners in the biology of the extracellular matrix (ECM) with experts in epilepsy research. This, therefore, represents a truly collaborative effort to determine not only the role of the ECM in the development of epilepsy but also novel approaches to treat and to prevent epilepsy.

Researcher(s)

• Promoter: Dedeurwaerdere Stefanie
• Promoter: Van Der Veken Pieter

Research team(s)

• Translational Neurosciences (TNW)
• Medicinal Chemistry (UAMC)

Project type(s)

• Research Project

Abstract

Each year, there are 1.5-2.0 million new cases of monocular corneal blindness due to ocular trauma and corneal ulceration. This includes 500 new cases in Flanders, while only 350 corneal transplants are performed annually. This project aims to develop biomimetic corneal constructs that will be fabricated using 3D printing and which will be seeded with corneal stem cells, which allows cost-effective manufacturing of customized structures with high resolution. This project will focus on innovation via interdisciplinary collaboration between production engineering, biomaterials and cell biology in ophthalmology in order to bring the 3D printed biocornea to a proof-of-concept. The overall goal is to create a biocornea that is optically transparent, with appropriate mechanical and geometric properties that can serve as a replacement for the existing use of cadaveric donor corneas

Researcher(s)

• Promoter: Tassignon Marie-Jose
• Co-promoter: Zakaria Nadia
• Fellow: Matthyssen Steffi

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Epilepsy is a devastating disorder affecting 50 million people worldwide characterised by recurrent seizures and serious psychiatric comorbidities such as anxiety and depression. This research proposal will investigate a novel hypothesis connecting brain inflammation and neurosteriod alterations as protagonists during the development of epilepsy and its comorbidities a process termed epileptogenesis. These former pathways are shown to have bimodal effects on seizure susceptibility, but up till now have only been investigated independently. Our hypothesis of coupling these pathways is supported by the observation that i) the translocator protein (TSPO) a marker of brain inflammation is highly upregulated in epilepsy and ii) the main function of TSPO is cholesterol import, the rate-limiting step in steroidogenesis. Firstly, we will for the first time investigate the brain region and cell specific distribution pattern of TSPO during epileptogenesis and established epilepsy in two rat models of acquired epilepsy. Secondly, pharmacological agents will be used to interfere with TSPO and brain inflammation to investigate a causal relationship between TSPO and epileptogenesis by means of translational techniques namely in vivo TSPO PET imaging, behavioural tests and video-EEG monitoring in a rat model of temporal lobe epilepsy. This innovative project will increase our understanding of the ambiguous complexities related to brain inflammation- and neurosteriod-induced effects on brain excitability potentially revealing an interrelated action. If the proposed hypothesis holds true, this may influence our current thinking regarding the role of brain inflammation in epilepsy and psychiatric conditions.

Researcher(s)

• Promoter: Dedeurwaerdere Stefanie
• Fellow: Bertoglio Daniele

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

The overall aim of this project is to develop a scaffold with collagen nanofibre alignment to replace the existing use of human amniotic membranes for ocular surface reconstruction. The expected outcome is a standardized prototype composite graft with improved transparency, mechanical strength, bio-integration and reduced microbial susceptibility, realised through combining biomaterials engineering, protein surface modification and stem cell technologies. During the course of this research we intend to bring this prototype to a proof-of-concept in a rabbit model of limbal stem cell deficiency. This cutting-edge research will lay the groundwork for the development of sustainable biomimetic artificial corneas through an extension of its engineering.

Researcher(s)

• Promoter: Tassignon Marie-Jose
• Co-promoter: Zakaria Nadia
• Fellow: Haagdorens Michel

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

MMPs comprise a family of zinc-dependent peptidases involved in the remodelling and degradation of the ECM. MMP-9 has been identified as emerging molecular system involved in epileptogenesis. In vivo PET imaging is a powerful non-invasive tool to monitor the metabolism and properties of drugs in (pre)clinical trials. We will synthesize and evaluate the in vitro/in vivo properties of several potential MMP-9 radiotracers for brain imaging.

Researcher(s)

• Promoter: Vázquez Naiara

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

The overall goal is to create a bio-cornea that is optically transparent, with appropriate mechanical and geometric properties. Bio-compatability and integration will be determined in in vivo rabbit models of corneal transplantation. This project will focus on innovation via interdisciplinary collaboration between production engineering, biomaterials, and cell biology in ophthalmology in order to bring the 3D printed bio-cornea to a proof-ofconcept.

Researcher(s)

• Promoter: Tassignon Marie-Jose
• Co-promoter: Zakaria Nadia

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Epilepsy is a devastating disorder affecting 50 million people worldwide. This research project will investigate a novel hypothesis connecting brain inflammation and neurosteriod alterations as key processes during epileptogenesis. These two pathways are shown to have bimodal effects on seizure susceptibility, but up till now have only been investigated independently.

Researcher(s)

• Promoter: Dedeurwaerdere Stefanie

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Epilepsy is a devastating disorder affecting 50 million people worldwide. This research project will investigate a novel hypothesis connecting brain inflammation and neurosteriod alterations as key processes during epileptogenesis. These two pathways are shown to have bimodal effects on seizure susceptibility, but up till now have only been investigated independently.

Researcher(s)

• Promoter: Dedeurwaerdere Stefanie

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

This project represents a formal research agreement between UA and on the other hand UZA. UA provides UZA research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

• Promoter: Wyndaele Jean Jacques
• Fellow: Yu Tian

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

We propose a novel hypothesis for the development of PTE with a central role for ECM modulating components MMP-9 and uPA. TBI results in blood-brain barrier disruption, hyperexcitability and primary damage triggering repair mechanisms such as modulation of the ECM by proteases MMP-9 and uPA. These alterations in ECM proteases MMP-9 and uPA, followed by brain inflammation, induce abnormal synaptic remodeling and epileptogenesis, ultimately leading to PTE.

Researcher(s)

• Promoter: Dedeurwaerdere Stefanie
• Co-promoter: Staelens Steven
• Fellow: Missault Stephan

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

This project represents a formal research agreement between UA and on the other hand UZA. UA provides UZA research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

• Promoter: De Wachter Stefan
• Promoter: Wyndaele Jean Jacques
• Fellow: Eggermont Monica

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

In the present project we aim at testing a hypothesis that MMP-9 and uPA/uPAR contribute to circuitry remodeling during post-traumatic epileptogenesis. We focus on those two molecular systems, because there is a strong support for their involvement in other models of epileptogenesis, as well as the partners of this consortium have excellent tools and expertise to investigate these molecules.

Researcher(s)

• Promoter: Dedeurwaerdere Stefanie

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

This project represents a formal research agreement between UA and on the other hand UZA. UA provides UZA research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

• Promoter: De Wachter Stefan
• Promoter: Wyndaele Jean Jacques

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

This project represents a formal research agreement between UA and on the other hand a private institution. UA provides the private institution research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

• Promoter: Dedeurwaerdere Stefanie

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

The current project will follow the development of neuroinflammation together with functional brain integrity and behavioural outcome in a rodent model of maternal immune activation in vivo utilising state-of-the-art multimodal imaging biomarkers.This project will generate highly novel information about the contribution of neuroinflammation to the development of schizophrenia and its consequences for the functional integrity of the brain, and eventually provide a rationale for the implementation of novel disease-modifying strategies.

Researcher(s)

• Promoter: Dedeurwaerdere Stefanie
• Co-promoter: Staelens Steven
• Co-promoter: Timmermans Jean-Pierre
• Co-promoter: Van Der Linden Annemie

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

The central question in the present proposal is how humans generate an auditory conscious percept and what the neural correlates of auditory conscious percept are. The research method is based on functional imaging with quantitative electroencephalography and PET scans in people with normal hearing, individuals with a cochlear implant because of deafness, and those with phantom sound with a cortical implant. This project aims to contribute to the understanding of auditory consciousness specifically and consciousness at large.

Researcher(s)

• Promoter: Van de Heyning Paul
• Co-promoter: De Ridder Dirk

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Various brain injuries in humans are associated with the acute occurrence of seizures and an increased risk of developing epilepsy after a latent period. An important feature regulating the reorganization of the neuronal network after the occurrence of a neuronal insult is neuroinflammation. Most recently, the hypothesis has been postulated that inflammatory processes within the brain mght constitute a common and crucial mechanism in the pathophysiology of seizures and epilepsy. Advances in small animal imaging allow researchers, for the first time, to study structural and functional changes during the development of epilepsy in living animals. This comprehensive innovative project will develop thorough in vivo methodologies with histological validation in a rodent model for temporal lobe epilepsy. Following, a longitudinal study will allow investigating the development of structural brain abnormalities and neuroinflammation in relation to the occurrence of epileptic seizures utilising in vivo PET/MRI imaging. In a last phase, the project will set a translational framework for evaluating novel anti-inflammatory therapies using a multimodal imaging approach, which will facilitate transferring knowledge from bench to bed. Briefly, this project may lead to novel diagnostic imaging biomarkers for the identification of patients at risk and provide rationale for neuroprotective treatment strategies.

Researcher(s)

• Promoter: Dedeurwaerdere Stefanie

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

The neurobiological processes that eventually result in epilepsy are still not completely understood. It is well known that brain injuries such as neurotraumata, febrile seizures, infection and status epilepticus are associated with the acute occurrence of seizures and a higher risk of developing epilepsy after a latent period. Recent studies strongly support the hypothesis that brain inflammation plays an important role in the pathophysiology of seizures and epilepsy. The asset of this comprehensive study is that it will employ the recent progress made in non-invasive small animal imaging to characterize brain inflammation in a chronic epilepsy model. First of all the project aims to characterize this process by traditional postmortem techniques. In the following step in vivo methodologies will be developed with histological validation to assess brain inflammation, brain activity and structural brain abnormalities. In the next step, structural changes in the brain together with inflammation will be longitudinally followed up during the development of epilepsy in living animals by PET/MRI imaging. Finally, the effect of different pharmacological interventions on brain inflammation will be investigated by PET/MRI imaging. Thus, this project will lead to a better understanding and characterization of the role of brain inflammation in epilepsy, which will impact development and evaluation of novel treatment strategies in the field.

Researcher(s)

• Promoter: Dedeurwaerdere Stefanie
• Fellow: Amhaoul Halima

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Consciousness is one of the greatest mysteries unresolved by neuroscience. Perceiving auditory stimuli with a meaning consciously is a crucial sensory perception. Understanding the brain mechanisms involved in auditory conscious perception, such as noise and tones is crucial for gaining knowledge about consciousness. Hearing is performed primarily by the auditory system. It has been shown that activity in the auditory cortex is necessary, but not sufficient for auditory consciousness. In order to perceive an auditory stimulus consciously different brain networks need to be co-activated. In this project I try to map and disentangle these different brain networks, and determine their exact function related to consciousness by including three populations, one without auditory consciousness (deaf people), one with normal auditory consciousness and one with too much auditory conscious percepts (phantom sounds). Auditory stimulus presentation just below, at and above hearing threshold will be analyzed using different neuroimaging and neuromodulation techniques. This research project fundamentally contributes to understanding the neurobiological mechanisms involved in auditory conscious perception. Secondly, it contributes to a new approach in neuroscience by introducing network science technology in consciousness research and thirdly, it might help in the development of new diagnostic tools and treatments for patients with auditory disorders.

Researcher(s)

• Promoter: Van de Heyning Paul
• Co-promoter: De Ridder Dirk
• Fellow: Vanneste Sven

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative brain disorder. Five causal genes (SNCA, LRRK2, PARK2, PINK1 and DJ1) leading to familial PD have already been identified. Variations in these genes have also been shown to increase susceptibility for sporadic PD. In my project, I am prospectively recruiting a population of familial and sporadic PD patients. Detailed phenotypic characterization of the patients is performed with standardized clinical scales at different time intervals. Genetic variations (simple and complex mutations) in the known causal genes will be identified and genotype-phenotype correlations will be established. Since disease progression is an important part of the phenotypic variability of PD, these correlations will focus on clinical features associated with disease progression, non-motor symptoms and motor complications. Genetic association studies will be conducted to identify new genetic risk factors for PD. In informative families new causal PD genes will be identified using a positional cloning strategy. The combination of objective and longitudinal clinical data on disease progression in a genetically well-characterized population of PD patients, is a major asset of the project.

Researcher(s)

• Promoter: Cras Patrick
• Co-promoter: Van Broeckhoven Christine
• Fellow: Crosiers David

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Chronic neurological diseases such as epilepsy and schizophrenia are difficult to manage and severely disabling disorders. Moreover, they are putting a huge burden on our social health care system. Currently, there is no available therapy that effectively halts or retards the development or progression of these conditions. The more we learn, the more it becomes clear that these neurological diseases are extremely complex as they do not have a well-understood mechanism of action and perhaps diverging dysfunctions, with evolving temporal and spatial aspects, may contribute to the disease. Remarkably, the manifestation of both diseases is preceded by a seemingly "silent" or "latent" period of several years without any apparent symptoms. Interestingly, scientific research suggests that this could be related to a neuronal insult during a critical phase of life, which initiates a series of pathophysiological processes during the latent period. At current, little research has been directed to investigate the latent period. As in patients, the chronic stage of the disease is represented rather than the early stage, the human research endeavour has been limited due to the difficulty to set-up these type of long-term prospective studies. As a consequence, our understanding of the processes occurring during this critical phase of the development of the disorder is incomplete. For instance, it is unknown what factors contribute to the phenomenon that only a subgroup of individuals will eventually be affected by the disorder. A better insight in these events could potentially lead to early identification of patients at risk. It has been speculated that neuroinflammation plays an important role in the reorganisation of the neuronal network after the occurrence of a traumatic event. The current project will follow the development of neuroinflammation together with the investigation of the functional integrity of the brain in laboratory animals utilising imaging biomarkers. The recent advances in dedicated in vivo imaging techniques for small animal brain imaging, such as positron emission tomography (PET), allow scientist for the first time to conduct basic research in a non-invasive and longitudinal manner, facilitating translation of knowledge from bench side to clinical application. This study will add very important new information about the contribution of neuroinflammation to the development of neurological disorders such as epilepsy and schizophrenia, its consequences for the functional integrity of the brain and whether these biomarkers could contribute to the early identification of patients as risk. Non-invasive imaging using biomarkers is an upcoming and promising new approach, which clearly allows for translation of applications to the clinic. The outcomes of this research will inform clinical practice, particularly providing rationale for the implementation of potentially neuroprotective strategies to slow down or halt this degeneration, as well as potentially providing a method to assess the biological efficacy of prospective new therapies prior to the institution of expensive human trials.

Researcher(s)

• Promoter: Dedeurwaerdere Stefanie
• Co-promoter: Kumar-Singh Samir
• Co-promoter: Staelens Steven

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

This project represents a formal research agreement between UA and on the other hand UZA. UA provides UZA research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

• Promoter: Wyndaele Jean Jacques
• Fellow: Chaitanya Gopinath

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

During this project, motor training will be combined with non-invasive brain stimulation in stroke patients. By means of a double-blind, sham-controlled study the effect of additional static balance training which makes use of visual feedback in combination with transcranial Direct Current Stimulation on postural control in stroke patients is examined. This project will contribute to the implementation of a new treatment modality in clinical practice.

Researcher(s)

• Promoter: Van de Heyning Paul
• Co-principal investigator: Hallemans Ann
• Co-principal investigator: Vereeck Luc

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

The aim of the project is to i) set-up chronic animal models for different neurological diseases, ii) to establish specific, but also common biomarkers for these diseases using in vivo imaging modalities (focusing on small animal PET imaging) and validation with histological techniques, iii) follow-up disease progress using these in vivo biomarkers in conjunction with bio-imaging, and iv) to evaluate treatment response using these in vivo biomarkers with bio-imaging.

Researcher(s)

• Promoter: Dedeurwaerdere Stefanie
• Fellow: Dedeurwaerdere Stefanie

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

This project represents a formal research agreement between UA and on the other hand UZA. UA provides UZA research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

• Promoter: Wyndaele Jean Jacques
• Fellow: Chaitanya Gopinath

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

This project represents a formal research agreement between UA and on the other hand the Flemish Public Service. UA provides the Flemish Public Service research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

• Promoter: Van de Heyning Paul
• Co-promoter: Aerts Peter
• Co-promoter: Pieters Luc
• Co-promoter: Truijen Steven
• Co-promoter: Wuyts Floris

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Braem Marc

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Endothelin-1 is being increasingly recognized as an important molecule in the development and progression of cancer, but also in the occurrence of cancer pain. So far, all studies have used acute administration of ET-1, bearing little resemblance with the prolonged exposure observed in clinical conditions. It is therefore proposed to investigate the effects of chronic exposure to ET-1 on signs of spontaneous and evoked pain behaviour.

Researcher(s)

• Promoter: Deseure Kristof
• Co-promoter: Hans Guy
• Co-promoter: Vercauteren Marcel P E

Research team(s)

• Translational Neurosciences (TNW)
• Antwerp Surgical Training, Anatomy and Research Centre (ASTARC)

Project type(s)

• Research Project

Abstract

This project represents a formal research agreement between UA and on the other hand UZA. UA provides UZA research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

• Promoter: Wyndaele Jean Jacques
• Fellow: Minagawa Tomonori

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Many stroke survivors have residual physical impairments that may lead to a sedentary lifestyle and consequently a decline in cardiorespiratory fitness. Research is needed to determine the optimal protocol to train individuals with different levels of physical impairment and cardiac risk. It is useful to know the long-term effects of aerobic exercise training as well as the relationship between improvement in aerobic capacity and daily function.

Researcher(s)

• Promoter: Cras Patrick
• Co-principal investigator: Truijen Steven

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

This project represents a formal research agreement between UA and on the other hand UZA. UA provides UZA research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

• Promoter: Wyndaele Jean Jacques
• Fellow: Kaerts Nore

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

This project represents a formal research agreement between UA and on the other hand UZA. UA provides UZA research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

• Promoter: Van de Heyning Paul
• Fellow: Desmet Jolien

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Neurocritical care has become a distinct discipline within the field of intensive care medicine with a major focus on the treatment of patients with acute damage to the most complex organ of the human body, the brain. The main indications for acute neurocritical care concern aneurysmal Subarachnoid Hemorrhage (SAH) and severe Traumatic Brain Injury (TBI). These disease entities form a major health and socioeconomic problem as they afflict young patients and the rate of death and disability is high. The pathology and treatment of these patients is heterogeneous and complex. Despite advances in basic neuroscience which have increased our understanding of processes in the injured brain, approaches to management are largely unfocused and adhere to the concept of a 'one pill for everybody' approach. Novel monitoring technology and new neuroimaging techniques now offer opportunities for advancing the care for these patients to a more individualized targeted management. This proposal concerns a prospective translational study in patients with SAH or TBI requiring neurocritical care. The global aim is to develop recommendations for individualized targeted management. We aim to enrol a total of 50 patients over a 2-year period. We will implement extensive monitoring in these patients, including electrocorticography, continuous monitoring of cerebral blood flow and oxygenation and perform extensive neuroimaging studies. The various monitoring modalities will each provide a different and complementary perspective to the complex problems in acutely brain damaged patients, as well as into the interaction between systemic and cerebral effects. Neuroimaging studies will provide accurate characterization of structural damage and serve as early endpoints for documentation of ischaemic damage and for differentiating the degree of swelling from ischaemia. Extensive within– and between– patient analyses will be conducted to assess the sensitivity of monitored parameters for detecting impending deterioration and to quantify the added benefits of extended monitoring and sensitivity of these parameters under different disease conditions. The major novelty in this project is the concept of an integrated approach towards individualized targeted management in neurocritical care. This concept carries a high potential for improving treatment and outcome for these patients. Collaboration with international partners will be established for specific items of this project and this will additionally serve to establish the position of neurocritical care in Flanders on an international level.

Researcher(s)

• Promoter: Maas Andrew

Research team(s)

• Translational Neurosciences (TNW)

Project website

Project type(s)

• Research Project

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative brain disorder. Five causal genes (SNCA, LRRK2, PARK2, PINK1 and DJ1) leading to familial PD have already been identified. Variations in these genes have also been shown to increase susceptibility for sporadic PD. In my project, I am prospectively recruiting a population of familial and sporadic PD patients. Detailed phenotypic characterization of the patients is performed with standardized clinical scales at different time intervals. Genetic variations (simple and complex mutations) in the known causal genes will be identified and genotype-phenotype correlations will be established. Since disease progression is an important part of the phenotypic variability of PD, these correlations will focus on clinical features associated with disease progression, non-motor symptoms and motor complications. Genetic association studies will be conducted to identify new genetic risk factors for PD. In informative families new causal PD genes will be identified using a positional cloning strategy. The combination of objective and longitudinal clinical data on disease progression in a genetically well-characterized population of PD patients, is a major asset of the project.

Researcher(s)

• Promoter: Cras Patrick
• Co-promoter: Van Broeckhoven Christine
• Fellow: Crosiers David

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Van de Heyning Paul
• Co-promoter: Wuyts Floris
• Fellow: Blaivie Catherine

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

IMPACT: International Mission for Prognosis and Analysis of Clinical Trials in TBI. Traumatic Brain Injury (TBI) may afflict us all, but young adult males are particularly at risk. IMPACT is an international multidisciplinary effort to advance clinical research programmes in search of better treatment. Nearly 10 years of work has resulted in the development of a prognostic calculator for establishing prognosis in individual patients, proposals for standardization of data collection in TBI studies (common data elements) and recommendations for improving the design and analysis of TBI studies. It is hoped that these recommendations will substantially increase possibilities for proving efficacy of new treatments. We greatly welcome any feedback you may have Background Traumatic Brain Injury (TBI) is a dynamic and heterogeneous disease in which many mechanisms and pathways can lead to secondary damage. Many different kinds of therapy and neuroprotective agents with high potential for efficacy have been developed. Unfortunately in trials none of these have shown convincing evidence of benefit in the clinical situation with sufficient generalizibility. Some of these therapies may have been truly ineffective but the risk exists that some therapies may have been wrongly discarded due to the use of insensitive methodology in clinical trials. The TBI population poses several complicated methodological challenges, related to the heterogeneity of the population, outcome-assessment and design issues. IMPACT is focused on tackling these head-on with the aim of providing recommendations for more powerful trials in the future.

Researcher(s)

• Promoter: Maas Andrew
• Fellow: Roozenbeek Bob

Research team(s)

• Translational Neurosciences (TNW)

Project website

Project type(s)

• Research Project

Abstract

Neurocritical care has become a distinct discipline within the field of intensive care medicine with a major focus on the treatment of patients with acute damage to the most complex organ of the human body, the brain. The main indications for acute neurocritical care concern aneurysmal Subarachnoid Hemorrhage (SAH) and severe Traumatic Brain Injury (TBI). These disease entities form a major health and socioeconomic problem as they afflict young patients and the rate of death and disability is high. The pathology and treatment of these patients is heterogeneous and complex. Despite advances in basic neuroscience which have increased our understanding of processes in the injured brain, approaches to management are largely unfocused and adhere to the concept of a 'one pill for everybody' approach. Novel monitoring technology and new neuroimaging techniques now offer opportunities for advancing the care for these patients to a more individualized targeted management. This proposal concerns a prospective translational study in patients with SAH or TBI requiring neurocritical care. The global aim is to develop recommendations for individualized targeted management. We aim to enrol a total of 50 patients over a 2-year period. We will implement extensive monitoring in these patients, including electrocorticography, continuous monitoring of cerebral blood flow and oxygenation and perform extensive neuroimaging studies. The various monitoring modalities will each provide a different and complementary perspective to the complex problems in acutely brain damaged patients, as well as into the interaction between systemic and cerebral effects. Neuroimaging studies will provide accurate characterization of structural damage and serve as early endpoints for documentation of ischaemic damage and for differentiating the degree of swelling from ischaemia. Extensive within– and between– patient analyses will be conducted to assess the sensitivity of monitored parameters for detecting impending deterioration and to quantify the added benefits of extended monitoring and sensitivity of these parameters under different disease conditions. The major novelty in this project is the concept of an integrated approach towards individualized targeted management in neurocritical care. This concept carries a high potential for improving treatment and outcome for these patients. Collaboration with international partners will be established for specific items of this project and this will additionally serve to establish the position of neurocritical care in Flanders on an international level.

Researcher(s)

• Promoter: Maas Andrew

Research team(s)

• Translational Neurosciences (TNW)

Project website

Project type(s)

• Research Project

Abstract

The purpose of this study is to examine whether a prolonged conflict between motor activity and sensory feedback triggers sensitization of the central nervous system, and whether it plays an aetiological role in the transition from acute to chronic whiplash pain. Study participants will enter a 6-months prospective longitudinal study. They will examined at 3 different occasions (within 2 weeks after the whiplash trauma, and 2 and 6 months post-whiplash).

Researcher(s)

• Promoter: Cras Patrick
• Co-principal investigator: Roussel Nathalie

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Endothelin-1 is being increasingly recognized as an important molecule in the development and progression of cancer, but also in the occurrence of cancer pain. So far, all studies have used acute administration of ET-1, bearing little resemblance with the prolonged exposure observed in clinical conditions. It is therefore proposed to investigate the effects of chronic exposure to ET-1 on signs of spontaneous and evoked pain behaviour.

Researcher(s)

• Promoter: Deseure Kristof

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

This project represents a formal research agreement between UA and on the other hand UZA. UA provides UZA research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

• Promoter: De Ridder Dirk
• Fellow: Vanneste Sven

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

The lower urinary tract symptoms, including those of the overactive bladder syndrome, increase after menopause, when the lack of estrogen results in both functional and structural changes in the lower urinary tract (LUT). Its is possible that lack of estrogen increases afferent nerve activity from the LUT but this is not certain at all. If an effect would be present can it then be counteracted by estrogen treatment. To investigate this, we will use direct recording of afferent nerve activity from the LUT through both A and C-fibers with single fiber electrophysiological technique.

Researcher(s)

• Promoter: Wyndaele Jean Jacques
• Fellow: Aizawa Naoki

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

The development en validation of head and bodypositioning technology in strokepatients. The relationship between this posture and falling is investigated. In particular processes of equilibrium and neuropsychology are studied. Acquired knowledge is implemented in therapy and is subsequently evaluated.

Researcher(s)

• Promoter: Van de Heyning Paul
• Co-principal investigator: Truijen Steven
• Co-promoter: Wuyts Floris

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Vermandel Alexandra

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Wyndaele Jean Jacques
• Fellow: Naoemova Irina

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

The objective evaluation of voice quality relies mainly on acoustic parameters. At present, this analysis is based on a sustained vowel. This is an unrealistic approach since human communication is running speech by definition. The development of an objective acoustic correlate based on running speech would be a huge step forward in a more realistic objective assessment of voice and hoarseness in the ENT-practice.

Researcher(s)

• Promoter: Van de Heyning Paul

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Deseure Kristof

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Electrical stimulation is used for diagnosis in the lower urinary tract and for treatment of different urological pathologies. In the vast majority square wave pulses are used but with limited success. We explore the use of alternative types of electrical current which can be more specific and more physiological both in electro diagnosis as in electrotherapy.

Researcher(s)

• Promoter: Wyndaele Jean Jacques
• Co-promoter: De Wachter Stefan
• Co-promoter: Peeters Stefaan

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Specific aims of the project: 1) determine the autonomic nervous system neural circuit involved in maladaptive and adaptive tinnitus coping; 2) determine some of the main neuroendocrine components in maladaptive and adaptive tinnis coping; 3) determine the causal relationship of autonomic nervous system activation in non-coping tinnitus by comparing tinnitus-on and tinnitus-off situations in the same patients, 4) develop a theoretical conceptual framework of autonomic nervous system involvement in compensated and decompensated tinnitus based on 1,2 and 3.

Researcher(s)

• Promoter: Van de Heyning Paul
• Fellow: van der Loo Elsa

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

It has become clear that many health problems in the pelvic region in humans should be studied and treated globally taking into account interactions between systems and organs. There is also growing evidence that physical therapy of the pelvic region has an important role. We study the interactions of pelvic physiotherapy done for problems in one system on adjacent systems and the global effect on all systems together.

Researcher(s)

• Promoter: Wyndaele Jean Jacques

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Van de Heyning Paul

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Van de Heyning Paul
• Fellow: Vermeire Katrien

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: De Bodt Marc

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

This experiment is part of a larger interdisciplinary project in order to model complex data structures and the accompanying theoretical reference for reliable inferences. The project will implement flexible and reliable statistical models for the microbiological risk evaluations for zoonoses in the food chain.

Researcher(s)

• Promoter: Cras Patrick

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Van de Heyning Paul

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Otosclerosis is a common bone abnormality of the otic capsule, characterized by abnormal resorption and redeposition of bone. Two types of otosclerosis can be distinguished: histological and clinical otosclerosis. Histological otosclerosis refers to the presence of otosclerosis, diagnosed post mortem by histological survey of temporal bones. Clinical otosclerosis refers to the presence of conductive or mixed hearing loss caused by stapedial fixation or round window abnormalities. An important discrepancy exists in the prevalence of both forms, 2.5% for histological otosclerosis and 0.3% for clinical otosclerosis, respectively. Therefore, otosclerosis is clearly under-diagnosed in clinical practice (factor 8!). This discrepancy between histological and clinical otosclerosis is caused by the variable topography of the otosclerotic foci in the otic capsule: not all localisations cause a typical symptomatology. A fenestral otosclerosis (oval or round window) is relatively easily diagnosed with audiometrical and tympanometrical techniques. In this case, a conductive or mixed hearing loss is present, whether with or without a typical Carhart notch. When the otosclerotic foci occur somewhere else in the otic capsule, the so called `cohlear otosclerosis' is difficult to distinguish audiometrically from other forms of perceptive hearing loss. By using radiological imaging techniques, the diagnosis of cochlear otosclerosis can be made in some cases, but usually no radiological symptoms are visible. In conclusion, due to the high prevalence among the population there is a current need for a more sensitive and more specific diagnosis of cochlear otosclerosis, both clinically as well as radiologically. In addition, otosclerosis appears to be a genetically complex disease caused by an interaction of genes and environmental factors. However, knowledge regarding the influence of this interaction is insufficient, but is probably partially underlying the heterogeneous fenotypic characteristics. Further classification of these otosclerotic subfenotypes is a conditio sine qua non for the clinical diagnostics. When scientific research succeeds in pin-pointing environmental or genetic risk factors and correlating these factors with fenotypic characteristics the foundation is laid. The fundamental insights in the aetiology of otosclerosis and the more concrete classification of otosclerosis-subfenotypes gained by this project, will allow the ORL-clinicians to make a more specific diagnosis. In this way, the current symptomatic approach of otosclerosis will evolve to a more individual-specific approach.

Researcher(s)

• Promoter: Van de Heyning Paul
• Co-promoter: Parizel Paul
• Co-promoter: Van Camp Guy
• Fellow: Van Den Bogaert Kris

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

For the first time we will try to extrapolate in this study the basic findings concerning the role of Endothelin-1 as a pain mediator towards humans. For this purpose the development and time progression of a cutaneous hyperalgesia will be examined in healthy volunteers. In order to perform these investigations we will be using state of the art neurophysiological research techniques, such as quantitative sensory testing.

Researcher(s)

• Promoter: Hans Guy

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

This project involves -1- the collection of normative data and the validation of a clinical protocol to assess postural control in patients after a unilateral vestibular deafferentiation and -2- the study of short- and longterm effects after administration of specific, customized vestibular rehabilitation program in the acute phase after resection of an acoustic neuroma.

Researcher(s)

• Promoter: Van de Heyning Paul
• Co-promoter: Wuyts Floris

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

The aim of the project is to investigate the role of growth factors secreted by lens fiber cells (LFCs) in the proliferation and differentiation of lens epithelial cells (LECs) left in the capsular bag after extra-capsular cataract extraction (ECCE) and intra-ocular lens (IOL) implantation and the pathophysiology of posterior capsule opacification (PCO) or after cataract. Capsular bags obtained after ECCE on post mortem donor eyes will be cultured according to Wormstone et al. (1997).

Researcher(s)

• Promoter: Tassignon Marie-Jose

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

In this model, the potent vasoconstrictor Endothelin-1 (ET-1) will be administered to the infra-orbital nerve (IoN) of male Sprague-Dawley rats. The infra-orbital nerve of the rat is indeed extremely suited for the investigation of neuropathic pain syndromes because the IoN has a entirely sensoric function, without any motor function. This offers a great advantage compared to the often used sciatic nerve, which consists of a combination of motor and sensory components. Furthermore, clinical manifestation of a IoN injury induced pain syndrome can be fairly easy measured and investigated in a laboratory setting. Application of ET-1 will probably result in occurrence of spontaneous and evoked neuropathic pain symptoms in the facial area of the rats. After application of ET-1 to the IoN of the rat, animals will be tested for the presence of spontaneous pain (determination of spontaneous face-grooming behavior), as well as evoked pain sensations (after mechanical and thermal stimulation). Pain symptoms after innocuous mechanical stimulation (mechanical allodynia) will be induced by stimulating the facial area (zone I-II-III) with increasing sizes of von Frey hairs. For the investigation of the development of thermal allodynia we will use an entirely new method of investigation. Indeed, until now, thermal stimulation was almost never applied in laboratory settings due to the lack of standardization and reproducibility. In recent months we particpated in the development of system to apply short and well-defined thermal stimuli by remote control (in order to avoid the occurrence of sensitization on repeated stimulation in the animals). Hereby, we can apply a very precise repeatable stimulus to the animal. We can do this in two possible ways. Option 1: Apply a set amount of heat for a set amount of time. This can be set by the user and changed at any time. Option 2: Increasing controlled amount of heat. The user can set a starting temperature, a cutoff temperature and the ramp time. We can set a cutoff temperature to reduce the risk of tissue and nerve damage. Once the animal reacts the user can stop the stimulus and the temperature and time would be recorded automatically. In option 1 the one thing I would like to mention is that the heat source would need a very short amount of time to reach its set temperature, (something less than one second). The time of the stimulus can also be changed at anytime. The reaction of the animal will then be determined by the experimenter. The implementation of this method will mean that for the very first time rats can be objectively tested for the presence of thermal hyperalgesia and/or allodynia! Our lab will be the first lab in the world to be able to perform this sophisticated way of performing thermal testing in rats. The possibility of being able to investigate the presence and extent of thermal allodynia has to be considered as of extreme value since thermal allodynia is one of the most important characteristics of (common) clinical neuropathic pain syndromes. In addition, the infra-orbital nerve allows the use of several different methods of application of ET-1, which will provide us with extremely important ways of mimicking all kinds of both acute and chronic clinical conditions. More precisely, we will be able to perform extraneural application of ET-1 in acute (one single application of ET-1) and chronic conditions (implantation of osmotic pump in the surroundings of the IoN with continuous long-term application of very low doses of ET-1, mimicking the clinical 'ie. oncological- conditions). Also, intraneural application of ET-1 will be performed, as a model of intraneural invasion of tumor cells in clinical conditions. Finally, subcutaneous injection of ET-1 is possible in the facial area of the rat, which allows (electrophysiologic, morphological and biochemical) research into the pathophysiology of cutaneous hyperalgesia and allodynia (a condition seen in many oncological,

Researcher(s)

• Promoter: Hans Guy
• Co-promoter: Adriaensen Hugo

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Creutzfeldt-Jakob disease (CJD) belongs to the prion diseases and its pathogenesis shows some similarities with Alzheimer's disease (AD). Phosphorylated protein tau is found both in AD and CJD. The project examines the phosphorylation of tau in vitro and in an animal model.

Researcher(s)

• Promoter: Cras Patrick

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Creutzfeldt-Jakob's disease (CJD) is a human transmissible spongiform encephalopathy that is caused by an abnormal conformation of the prion protein (PrPsc) and is characterized by progressive dementia, myoclonus and other neurological symptoms. The present project investigates the mechanisms of tau phosphorylation in CJD, the detection of free radical formation, phosphorylation of tau in a scrapie model and differentiation of 14-3-3 isoforms.

Researcher(s)

• Promoter: Cras Patrick
• Fellow: Van Everbroeck Bart

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project