Research Benedicte De Winter

Abstract

Chronic inflammation plays a significant role in both the onset and progression of many diseases, including, but not limited to, cardiovascular disease, chronic infections, cancer, and inflammatory organ diseases such as COPD, NAFLD, and IBD. Furthermore, acute infections may also trigger chronic inflammation and associated long lasting sequelae. As the prevalence of these diseases is increasing in Western societies and also emerging in other regions, research in this area can have a profound societal and scientific impact. Regulated cell death, barrier dysfunction, and immune modulation are key drivers of chronic inflammatory processes (Fig. 1). There is growing evidence for a limited number of common molecular pathways underpinning the regulation of these processes, and hence for a complex interplay in their pathophysiology. In this regard, Infla-Med brings together UAntwerp's leading basic and translational researchers in these three domains to form a bench-to-bedside and back consortium. The collaboration of complementary forces has enabled scientific breakthroughs in inflammation-focused research and has proven crucial in leveraging collaborations and funding in this competitive research field. For instance, Infla-Med's first 'stage' (2016-2019) resulted in more than € 23M in awarded funding with an overall stable 45% success rate since 2016. Moreover, halfway through Infla-Med's second 'stage' (2020-2022), we have already acquired the same amount of competitive grants. In terms of excellence, Infla-Med's principle investigators have achieved remarkable success in securing large, highly competitive grants for interdisciplinary research at local (BOF-GOA/IMPULS), national (FWO-EOS, iBOF), and international (ERA.Net, Innovative Medicines Initiative, coordination of H2020-MSCA-ITN and HE-MSCA-DN projects) levels. This shows that Infla-Med has established a very high-performing synergistic research framework among its principle investigators. The next 'stage' of Infla-Med will focus on discovering additional scientific breakthroughs and increasing our involvement in leading international research networks and acquiring international excellence funding (ERC). Four key strategic decisions support these ambitious aims for Infla-Med's next stage.

Researcher(s)

• Promoter: De Meyer Guido
• Co-promoter: Caljon Guy
• Co-promoter: De Meester Ingrid
• Co-promoter: De Winter Benedicte
• Co-promoter: Francque Sven
• Co-promoter: Segers Vincent
• Co-promoter: Smet Annemieke
• Co-promoter: Vanden Berghe Tom
• Co-promoter: Van Der Veken Pieter
• Co-promoter: Wullaert Andy

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are characterized by chronic relapsing inflammation of the gastrointestinal tract in association with mucosal barrier dysfunction. A multitude of therapies are available, including biologicals which focus on reducing the inflammatory response, and recent novel small molecules, (e.g. Janus kinase (JAK) inhibitors) that have the potential to restore normal barrier function. However, the current knowledge does not help clinicians to choose the right therapy for the right patient, forcing them to do so empirically. As a result, 30% of the patients does not respond to the initial therapy and 50% loses response over time. According to the recent IBD guidelines, mucosal healing has been considered as a key therapeutic endpoint and encompasses the absence or resolution of inflammation and restoration of the mucosal barrier function. Mucosal healing currently involves endoscopic and histologic healing which, however, only measures the presence of inflammation without taking barrier function and thus the importance of barrier healing into account. Furthermore, objective measurements at the molecular level to monitor barrier healing are lacking and such molecular markers could also help clinicians in selecting the appropriate therapy. Mucins are the gatekeepers of the mucus barrier and are expressed at the apical surfaces of epithelial cells either as secretory or transmembrane mucins. These highly glycosylated proteins are uniquely endowed to interact with the extracellular environment and play an active role in the maintenance 3 of the mucosal barrier function. An imbalance in their expression pattern affects barrier integrity and dictates the development and course of disease. Furthermore, mucins are highly polymorphic and gene polymorphisms affecting mucin expression have been reported to influence the susceptibility towards IBD. The presence of genetic differences (e.g. SNPs) in mucin genes can give rise to a large repertoire of structurally diverse mRNA isoforms via alternative splicing of which some can alter protein function resulting in the progression towards disease. Such disease-associated mucin mRNA isoforms can thus act as novel molecular biomarkers to 1) mirror mucosal barrier healing on the one hand and 2) predict therapy response in IBD patients on the other hand. The functional and structural heterogeneity of mucin mRNA isoforms linked to IBD still remains an underexplored conundrum. Therefore, we recently designed a targeted mucin mRNA isoform sequencing approach to unravel the mucin mRNA isoform landscape in IBD and identified specific mucin mRNA isoform panels that associate with disease activity, IBD subtype (CD or UC) and anatomical location in the intestinal tract (terminal ileum, proximal colon, distal colon and rectum) with a high accuracy and that are therefore good candidate predictive biomarkers. In this project, we will further unravel cell-level insights in mucin isoform expression and thus the biology of alternative mucin splicing in IBD using available single cell sequencing datasets. Subsequently, we will investigate the potential clinical utility of the IBD-specific mucin mRNA isoform panels to monitor mucosal healing at the barrier level in IBD patients in comparison to the endoscopic and histological standards using preclinical (organoids) and translational setups and thus to investigate the functional capacity of our biomarkers.

Researcher(s)

• Promoter: De Winter Benedicte
• Co-promoter: Smet Annemieke

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

In a minority of patients with chronic stomach pain, long, spiral-shaped non-Helicobacter pylori helicobacters (NHPH) are found. These helicobacters colonize the stomach of humans and animals (such as dogs, cats and pigs) and are considered to have zoonotic potential. In the past, NHPH have been referred to as H. heilmannii sensu lato group, which includes several species: H. suis, H. felis, H. bizzozeronii, H. salomonis, H. heilmannii, H. cynogastricus and H. baculiformis. Previous work suggests a contributing factor in the etiology of various gastrointestinal diseases, ranging from chronic active gastritis without clinical symptoms to peptic ulceration, gastric adenocarcinoma, and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. NHPH bacteria are considered to also play a role in premalignant lesions of gastric cancer such as chronic gastritis, intestinal metaplasia and dysplasia. The exact prevalence of NHPH in these conditions is not clear. According to a recent study of our group, the prevalence of NHPH can vary between 20% to 25% in high risk patients and eradication with antibiotics can induce clinical and histological benefit in some patients. However up till now, 1/ no large multicenter prospective epidemiological studies on NHPH in patients with unexplained gastric disease exist, 2/ nor placebo-controlled randomized eradication studies for gastric NHPHs 3/ nor the impact of NHPH on the structural/functional heterogeneity of the mucin expression have been studied in the past and are therefore subject of the current PhD project. We would therefore link our expertise in mucin research with the topic of NHPHs in gastric disease. First, we will conduct a descriptive observational cross-sectional study on the prevalence of NHPH in high risk gastric patients. Second, a multicenter placebo-controlled randomized trial with antibiotics (Tryplera®) in NHPH positive patients will be performed in which the success rate of eradication and clinical, endoscopic and histological remission will be evaluated by means of standard genomic sequencing on target gastric biopsies. However, also new non-invasive tools as volatile organic compounds (VOCS) and genomic testing on saliva of patients will be tested for their diagnostic performance. Finally, the dynamics in mucins expression, that drive the evolution to more progressive gastric disease by causing enhanced inflammation and barrier dysfunction, will be studied and linked to the gastric microbial diversity and function (i.e. microbial-mucin mRNA isoform signature) in these well-defined gastric diseases and (pre-) malignancies in NHPH positive patients. Elucidating the pathogenic role of the NHPH and mucins in these associated diseases, can potentially improve the diagnosis and treatment of NHPH, can be beneficial to halt the progression towards gastric malignancy and can help patients with unexplained gastric symptoms.

Researcher(s)

• Promoter: De Winter Benedicte
• Co-promoter: De Schepper Heiko
• Fellow: Verstraelen Jona

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

Fibroblast activation protein (FAP) is a protease biomarker that is selectively expressed on activated fibroblasts. Strongly FAP-positive fibroblasts are present in > 90% of all tumor types, in fibrotic disease lesions, and in other pathologies that involve tissue remodeling. Researchers at UAntwerp earlier discovered UAMC1110: to date the most potent and selective FAP-inhibitor described. UAMC1110 is now used widely as the FAP-targeting vector of the so-called FAPIs: radiolabeled derivatives of UAMC1110. These FAPIs can be used as diagnostics or as therapeutics ('theranostics'), depending on the radiolabel. Many UAMC1110-derived FAPIs are currently in clinical development in oncology, 2 of which were co-developed preclinically by UAntwerp. While these FAPIs have shown impressive clinical results in oncodiagnosis, radiotherapy applications are somewhat lagging. This is because the original FAPIs typically have short FAP-residence times, leading to short tissue retention and fast wash-out of radioactivity. Druglikeness is not a critical parameter for most oncology applications, because of the leaky tumor vasculature and loose tissue. In very dense tissue, such as in fibrosis, druglikeness can however be expected to become a key parameter. The host recently discovered several series of druglike, pharmacophore-optimized FAPIs, for which 3 patent applications were submitted in 2022 and 2023. We wish to investigate these molecules further and exploit their improved FAP-residence and druglikeness in oncology and fibrosis theranostics settings.

Researcher(s)

• Promoter: Van Der Veken Pieter
• Co-promoter: De Meester Ingrid
• Co-promoter: De Winter Benedicte
• Co-promoter: De Winter Hans
• Co-promoter: Elvas Filipe
• Co-promoter: Francque Sven
• Co-promoter: Sterckx Yann
• Co-promoter: Stroobants Sigrid

Research team(s)

• Medicinal Chemistry (UAMC)

Project type(s)

• Research Project

Abstract

With this project, we will establish a Respiratory Virus Repository at the University of Antwerp. The collection of respiratory viruses will be available to companies, academic groups, and research institutions.

Researcher(s)

• Promoter: Delputte Peter
• Co-promoter: De Winter Benedicte
• Co-promoter: Van Hoorenbeeck Kim
• Co-promoter: Verhulst Stijn

Research team(s)

• Laboratory for Microbiology, Parasitology and Hygiene (LMPH)

Project type(s)

• Research Project

Abstract

Antimicrobial resistance is still one of the most serious global public health threats and is partly due to the inappropriate use of antibiotics. Acute respiratory tract infections (RTIs), affecting the upper respiratory system (e.g. sinusitis, pharyngitis and cold) or the lower part of the respiratory tract (e.g. acute bronchitis and pneumonia), are the main reasons for antibiotic prescription in primary care. Besides causing primary RTIs, bacterial and viral pathogens also play a paramount role in the exacerbations of chronic lung diseases such as chronic obstructive pulmonary disease (COPD). Due to the overlap in presentation of bacterial and viral acute RTIs and the lack of biomarkers that accurately distinguish between viral and bacterial RTIs, clinicians (i.e. pneumologists and intensivists) are forced to prescribe antibiotics to avoid missing a bacterial infection that could progress to a serious infection or sepsis. Furthermore, general practitioners do not always follow the recommended guidelines for antibiotic usage resulting in an overprescribing of antibiotics for self-limiting infections. Diagnostic uncertainty is thus a key contributor to antibiotic overuse that further fuels antimicrobial resistance. Novel biomarker assays discriminating bacterial from viral aetiology at the point-of-care still remain high unmet medical needs. Candidate novel biomarkers are the mucins. These highly glycosylated proteins are the gatekeepers of the mucosal barrier function maintaining epithelial cell homeostasis and act as a primary contact site to entrap microbes and facilitate their removal from the respiratory tract via a process called mucociliary clearance. However, upon bacterial and viral infection, aberrant mucin expression signatures forms a dysfunctional mucus barrier and becomes pathological. Next to this, mucins are highly polymorphic and the presence of genetic differences in the mucin genes can result in several mRNA isoforms of which some can be implicated in disease. Such disease-associated mucin mRNA isoforms can thus act as novel biomarkers to discriminate between bacterial and viral RTIs. Furthermore, given that epithelial cells can enter the bloodstream because of epithelial barrier injury, the peripheral blood provides a unique tool to monitor the levels of shed mucin mRNA isoforms among different patient groups. Indeed, we recently performed a proof-of-concept study in which we identified dynamic blood mucin mRNA isoform signatures that clearly distinguished symptomatic COVID-19 patients from patients with another viral RTI and discriminated between patients with mild and critical COVID-19. In this project, we wish to further unravel the complete peripheral mucin mRNA isoform landscape that associates with RTIs and identify mucin mRNA isoform biomarker panels that differentiate viral from bacterial RTIs using our optimized targeted mucin mRNA isoform sequencing approach in combination with random forest modelling on blood samples from patients with well-defined, well-characterized bacterial and/or viral RTIs.

Researcher(s)

• Promoter: Smet Annemieke
• Co-promoter: De Winter Benedicte

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

Inflammatory bowel diseases (IBD) are very heterogenous diseases that, due to their disabling and chronic nature and the high costs associated with their disease management, entail a great burden both for patients and for society. Currently, there are no available biomarkers to help clinicians choose the most appropriate treatment for each patient, forcing them to do so empirically. One way to improve treatment, is focussing on personalized medicine where efforts must be directed towards the identification of molecular markers to assess mucosal healing as the main therapeutic endpoint. According to the recent guidelines, mucosal healing is defined as a composite term of endoscopic improvement and histologic remission, but its evaluation still remains challenging as objective measurements at the molecular level to monitor mucosal healing and select the appropriate therapy are currently lacking. Novel molecular markers that could fit these criteria are the mucins. These highly glycosylated proteins are the gatekeepers maintaining mucosal barrier function. However, aberrant mucin expression, as characterized by a depletion of secreted mucin expression and overexpression of transmembrane mucins, has been described in IBD. Own data also highlighted that increased expression of MUC1, MUC3, MUC4 and MUC13 associates with IBD presentation and activity and is involved in barrier dysfunction by affecting expression of junctional proteins and cell polarity. Furthermore, mucins are highly polymorphic and the presence of genetic differences in the mucin genes can result in several mRNA isoforms of which some can be implicated in disease. In the context of the IOF-SBO (ID: 42601) and IOF-POC DEVELOP (ID: 48068) projects, we unraveled a mucin mRNA isoform landscape of 400 unique mucin mRNA isoforms that is 1) expressed in the intestinal tract of IBD and control patients and 2) includes mucin mRNA isoform panels that associate with disease/inflammatory status (IBD or control), IBD subtype (CD, UC) and location (ileum, colon). These panels were identified using our optimized targeted isoform nextgeneration sequencing (NGS) pipeline. In this project, we wish to further standardize our biomarker platform based on these mucin mRNA isoform panels. To do so, we will first introduce automation into our targeted isoform NGS workflow to minimize variability at library preparation level, eliminate pipetting errors and improve the throughput time, reproducibility, consistency and data quality. Subsequently, we will validate our mucin mRNA isoform panels on external clinical samples of different origin, such as biopsies, blood and stool, to evaluate their clinical efficacy as (minimally) invasive biomarkers predicting the probability of treatment success in IBD patients and thus to offer personalised medicine to the IBD population.

Researcher(s)

• Promoter: Smet Annemieke
• Co-promoter: De Winter Benedicte

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

Gastric cancer (GC) is the fifth most common cancer and the fourth leading cause of cancer-related death worldwide. Although Helicobacter pylori is the primary cause of GC, the disease is complex and involves multiple genetic, molecular, environmental, and microbiological factors. One of the hallmark features of gastric adenocarcinomas is aberrant mucin expression which drives tumorigenesis by influencing cellular growth and survival. Mucins are the gatekeepers of the mucus barrier covering the epithelium underneath and are heavily glycosylated. They are expressed at the apical surfaces of epithelial cells either as secretory or transmembrane mucins and play a crucial role in the maintenance of mucosal barrier homeostasis by communicating between the microbial flora and the mucosal immune system. Furthermore, these aberrantly expressed glycoproteins are also linked to the initiation, progression, and poor prognosis of GC. Of particular interest is the transmembrane MUC13 mucin. In healthy human beings, MUC13 is predominantly expressed in the intestines with only a very low level of expression in the stomach. In the diseased stomach, however, MUC13 expression is significantly upregulated by IL-1β (a key mediator in Helicobacter-related GC) and more specifically in adenocarcinoma and during the early events of the carcinogenesis process. Furthermore, MUC13 contains serine and tyrosine residues for potential phosphorylation and a protein kinase C consensus phosphorylation motif in its cytoplasmic domain that could play a critical role in tumorigenesis via cell signalling pathways that protect tumour cells from death. Currently, the exact role of MUC13 in the gastric carcinogenesis process remains poorly understood. From a certain point on, however, development of gastric adenocarcinoma may be H. pylori-independent, since colonization decreases in later steps of carcinogenesis, particularly in patients who develop intestinal metaplasia and dysplasia, and is finally lost in adenocarcinoma. Nowadays, the gastric microbiome is believed to contribute to cancer progression as well. The GC microbiome seems to be enriched with intestinal or oral taxa which can be assigned to an increase in pH, caused by H. pylori, and to specific interactions of the microbiota with the gastric mucosa. More specifically, the carbohydrate structures present on mucins, like MUC13, can act as binding sites or metabolic substrates for bacteria and the abundancy of MUC13 plays thus an important determinant in the site-specific colonization of bacteria in the gastric mucosa. Nevertheless, which specific tumour-enriched bacterial species can act as potential drivers in MUC13-mediated gastric carcinogenesis remains largely unknown. Therefore, this study aims to 1) identify the tumour-enriched bacterial taxa, other than H. pylori, involved in MUC13-driven gastric carcinogenesis and 2) unravel the MUC13-mediated mechanisms affecting tumour cell death.

Researcher(s)

• Promoter: Smet Annemieke
• Co-promoter: De Winter Benedicte
• Fellow: Oosterlinck Baptiste

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

With this project, we will establish a Respiratory Virus Repository at the University of Antwerp. The collection of respiratory viruses will be available to companies, academic groups, and research institutions.

Researcher(s)

• Promoter: Delputte Peter
• Co-promoter: De Winter Benedicte
• Co-promoter: Van Hoorenbeeck Kim
• Co-promoter: Verhulst Stijn

Research team(s)

• Laboratory for Microbiology, Parasitology and Hygiene (LMPH)

Project type(s)

• Research Project

Abstract

Volatile and semivolatile chemicals are recognised as byproducts of disease, boosting volatile analysis as paramount instrument to monitor health and disease, personalize health care and objectively establish the effect of different treatment strategies. Next to volatile organic compounds (VOCs), semivolatile compounds (SVOCS) are present in the environment and in biological matrices, but most of them need to be chemically and structurally identified and their role in health and disease is yet to be explored. In this proposal, we describe the set-up of a highend GCxGC-QTOF-MS facility for analysis of VOCs and SVOCs in biological samples like breath, blood, urine, faeces of humans and animals, and in the headspace of cells. The goal is to set up an infrastructure that allows to assess and investigate multiple biological sample types and their headspace for monitoring health and disease, to identify disease biomarkers, to intensify research on the environmental health issues of modern life, and to tackle the hurdles presently encountered in the metabolomics analysis of steroids and small organic acids. By this means, we intend to team up and complement with international volatomics research groups. In Flanders, such a specialised facility is lacking, and will be unique. It combines high sensitivity, ultralow detection limits for analysis and validation of the molecular composition of biological and headspace samples, with specific sampling devices and advanced data processing.

Researcher(s)

• Promoter: De Winter Benedicte
• Co-promoter: Covaci Adrian
• Co-promoter: Lamote Kevin
• Co-promoter: Lapperre Therese
• Co-promoter: Laukens Kris
• Co-promoter: Samson Roeland
• Co-promoter: van Meerbeeck Jan
• Co-promoter: van Nuijs Alexander
• Co-promoter: Wouters An

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

The Research Consortium of Excellence Infla-Med combines multidisciplinary expertise of eight research groups from two faculties to perform fundamental and translational research on inflammation, including: inflammatory gastrointestinal, cardiovascular, lung and kidney disorders, sepsis and allergies, as well as parasitic diseases, thereby focusing on specific inflammatory cell populations, including monocytes/macrophages, mast cells, basophils and lymphocytes. The approach of the Infla-Med consortium is twofold. Firstly, fundamental studies are performed to unravel the pathophysiological mechanisms underlying inflammatory conditions in order to enable more rational, targeted and effective intervention strategies. Secondly, Infla-Med aims to identify and validate novel therapeutic targets by screening chemical compounds in early drug discovery studies and by using an extensive platform of in vitro assays and in vivo models. The close collaboration with the Antwerp University Hospital (UZA) creates the opportunity to directly translate and clinically validate experimental findings. Thereby, Infla-Med contributes to two Frontline Research Domains of the University of Antwerp: 'Drug Discovery and Development' and 'Infectious Diseases'. Over the past four years, the multidisciplinary collaborations within Infla-Med have proven to be very successful and productive. By integrating the Infla-Med unique expertise on drug development, in vitro assays and clinically relevant animal models (validated with human samples), significant competitive funding has been acquired at European, national and UAntwerp levels with a success rate of more than 45%, which is far above the (inter)national average. Noteworthy, several Infla-Med projects have also made the transition towards valorization, demonstrating that Infla-Med results obtained from both fundamental research and well-designed preclinical studies can successfully be translated into clinical trials.

Researcher(s)

• Promoter: De Meyer Guido
• Co-promoter: Augustyns Koen
• Co-promoter: Caljon Guy
• Co-promoter: De Meester Ingrid
• Co-promoter: De Winter Benedicte
• Co-promoter: Ebo Didier
• Co-promoter: Heidbuchel Hein
• Co-promoter: Vanden Berghe Tom

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project website

Project type(s)

• Research Project

Abstract

The Laboratory of Experimental Medicine and Pediatrics - within the Faculty of Medicine and Health Sciences and closely linked to the Antwerp University Hospital - focusses its research on the study of inflammation in a clinically relevant context built on interdisciplinary methodologies and collaborations. To remain in the forefront of research we perform ground-breaking experimental, as well as clinical and translational research from bench to bedside and vice versa, using innovative and high-end methodologies including organoids, rodent models, cell cultures, different next-generation omics approaches and clinical trials. We challenge you to write down a project that will have an added value to one of the research lines currently explored at LEMP (www.uantwerpen.be/en/research-groups/lemp) and briefly described below. Loss of mucosal barrier integrity is a significant contributor in the pathophysiology of mucosal inflammatory/infectious diseases (e.g. IBD, gastrointestinal cancers, RSV, COVID-19). The role of transmembrane mucins, as epithelial signalling receptors mediating barrier dysfunction, is poorly understood. Furthermore, the presence of genetic differences in mucin genes can give rise via alternative splicing to a large repertoire of structurally diverse mucin mRNA isoforms encoding similar biological functions or altering protein function resulting in progression towards disease. Currently, the mucin mRNA isoform landscape implicated in mucosal barrier dysfunction is a field to discover. Volatile organic compounds (VOCs) are compounds that are by-products of cell metabolism and induced by inflammation. The human body houses thousands of VOCs which are exhaled and can serve as non-invasive markers for disease. Hence, breathomics is applied to search for clinically relevant diagnostic, prognostic and predictive biomarkers for inflammation-related diseases in adults and children (thoracic cancers, COVID-19, asthma, COPD, BPD in neonates, gastrointestinal diseases) and to monitor the effect of air pollution on human health. However, there is a need for further identification and data mining of volatiles, linking VOCs to metabolic processes. Chronic low-grade inflammation is a key factor in obesity. As its treatment remains challenging over all age groups, research focusses on new treatment strategies for obesity, that minimize dropout and weight regain. Pathophysiological processes (hypoxia) that lead to comorbidities like cardiovascular and metabolic morbidity and obstructive sleep apnoea are also of interest. Kidney transplantation is the best treatment for patients with end-stage renal disease. As diagnosis requires invasive procedures, there is a need of sensitive, non-invasive markers of an early-stage acute rejection and the early diagnosis of glomerular damage in children and adults with various underlying diseases (diabetes, obesity or sickle cell anaemia). Visceral pain is a key feature of the gastrointestinal disorders IBD and IBS. The management of visceral hypersensitivity is challenging and requires further research towards new treatment targets. Unravelling the immunopathogenesis of chronic Hepatitis B infections is essential in the quest for novel treatment approaches. While the ineffective T-cell responses are well-known, B cells have been left largely understudied, urging a deeper understanding of the role of the humoral immune response in chronic HBV at the level of HBV-specific antibody production and of the phenotypic/functional level of B cells. Non-Alcoholic Fatty Liver Disease (NAFLD) is the global leading cause of chronic liver disease but pharmacological treatment remains poorly successful. Changes in liver hemodynamics and in parenchymal oxygenation contribute to the steatohepatitis and progressive disease worsening and are a potential drugable target. Furthermore, the role of NAFLD on extrahepatic vascular alterations contributing to cardiovascular disease warrants further study.

Researcher(s)

• Promoter: De Winter Benedicte
• Co-promoter: Lamote Kevin
• Co-promoter: Ledeganck Kristien
• Co-promoter: Smet Annemieke
• Co-promoter: Van Eyck Annelies
• Fellow: Oosterlinck Baptiste

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

Inflammatory bowel diseases (IBD) are very heterogenous diseases that, due to their disabling and chronic nature and the high costs associated with their disease management, entail a great burden both for patients and for society. Currently, there are no available biomarkers to help clinicians choose the most appropriate treatment for each patient, forcing them to do so empirically. One way to improve treatment, is focussing on personalized medicine where efforts must be directed towards the identification of molecular markers to assess mucosal healing as the main therapeutic endpoint. Novel markers that could fit these criteria are the mucins. These highly glycosylated proteins are the gatekeepers maintaining mucosal barrier function. However, aberrant mucin expression, as characterized by a depletion of secreted mucin expression and overexpression of transmembrane mucins, has been described in IBD and own data highlighted that increased expression of MUC1, MUC3 and MUC13 is involved in barrier dysfunction by affecting expression of junctional proteins and cell polarity. Furthermore, mucins are highly polymorphic and the presence of genetic differences in the mucin genes can result in several mRNA isoforms of which some can be implicated in disease. The mucin mRNA isoform landscape associated with IBD still remains an unexplored conundrum. We have recently performed a proof of concept study in which we identified novel and known mRNA isoforms of MUC1, MUC3A, MUC5AC, MUC12, MUC13 and MUC17 associated with IBD. We wish to further validate our mucin mRNA isoform sequencing data to unravel the mucin mRNA isoforms as biomarkers to improve follow-up and treatment in IBD. Therefore, in this project we will design a mucin mRNA isoform-based biomarker assay to improve treatment management in IBD. To do so, we will first validate and complement our PacBio proof-of-concept isoform sequencing data and unravel which of the identified mucin mRNA isoforms are aberrantly expressed in IBD, using long-read ONT nanopore sequencing and short-read Illumina sequencing, respectively. These additional sequencing technologies will allow to select the optimal set of IBD-associated mucin mRNA isoforms for further implementation in a novel multiplex RT-qPCR-based biomarker assay. This biomarker assay will then be used to unravel which of the available and novel therapeutics impacts on aberrant mucin mRNA isoform expression and subsequent barrier function/integrity (as marker for mucosal healing) using patient-derived organoid cultures and to evaluate the efficacy of the IBD-associated mucin mRNA isoforms as minimally invasive biomarkers predicting the probability of treatment success at baseline in IBD patients.

Researcher(s)

• Promoter: Smet Annemieke
• Co-promoter: De Winter Benedicte

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

Exposure to air pollution is an important public health issue and has been associated with burden of disease, and increased mortality and morbidity. However, there is no safe threshold under which no health effects occur and only associations have been found so far. The goal of this pilot project is to prove the causal relation by assessing the impact of air pollution exposure on health and respiratory functioning, by combining air pollution monitoring with lung response measurements and exhaled breath analysis in order to minimize morbidity.

Researcher(s)

• Promoter: van Meerbeeck Jan
• Co-promoter: De Winter Benedicte
• Co-promoter: Lamote Kevin
• Co-promoter: Lapperre Therese
• Co-promoter: Samson Roeland

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

This gift will be used to fund research regarding thoracic oncology at LEMP. It will be used to fund consumables for these studies and includes biomarker research in persons and controls for which ethical approval has been obtained.

Researcher(s)

• Promoter: De Winter Benedicte

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

Next to inflammation, intestinal barrier dysfunction is an important mechanism related to the pathogenesis of inflammatory bowel diseases (IBD). The mechanisms underlying an altered barrier function in IBD, in particular the role of mucins (MUC), remain largely unexplored. Our own pilot data show an increased expression of MUC1 and MUC13 in inflamed biopsies from IBD patients. These MUCs are thought to disturb cell polarity complexes and tight junctions eventually resulting in an intestinal barrier dysfunction. Nevertheless, the exact role of MUC1 and MUC13 in the epithelial response to acute or chronic inflammation remains poorly understood. Therefore, we will first unravel the mechanisms by which these mucins affect intestinal barrier permeability upon inflammation using 3D-mini guts (organoids), the Ussing chamber technique and IBD mouse models. In parallel, the obtained results will be translated to IBD patients in order to identify MUC1 and MUC13 as novel targets for therapy and/or biomarkers, as still a large number of patients fail to respond or obtain full remission with the current therapies. To do so, the mechanisms of action of MUC1 and MUC13 affecting barrier integrity will be verified. Thereafter, the expression levels of MUC1, MUC13 and their barrier mediators will be investigated by single-cell RNA sequencing and subsequently correlated to the mucosal permeability and clinical outcome parameters.

Researcher(s)

• Promoter: Smet Annemieke
• Co-promoter: De Winter Benedicte
• Fellow: Ceuleers Hannah

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

Infection with SARS-CoV-2 mostly leads to a mild self-limiting respiratory tract illness, however, some patients develop severe progressive pneumonia, multiorgan failure, and death. This project aims to determine factors that dictate the course of COVID19 beyond cytokines. We have prior data that specific aberrantly expressed mucins, triggered by SARS-CoV-2, regulate ACE2 expression and affect lung barrier integrity. Such mucin alterations are clinically relevant as excessive mucin production is seen in severe COVID-19 illness obstructing the respiratory tract and complicating recovery. Here, we will first identify differentially expressed mucin isoforms in COVID-19 patients exhibiting the entire spectrum of disease severity. Thereafter, therapeutics currently used for COVID-19 will be screened for their ability to reduce mucin abundance. As mucin expression is also a critical factor in microbiome homeostasis and dysbiosis might modulate COVID-19 severity, this project secondly aims to map the microbiome associated with different degrees of disease severity. Unravelling mucin isoform-microbiome interactions that shape the course of SARS-CoV-2 infection will lead to the future identification of those patients who are in danger of progressing to severe disease. This project will also improve the choice for an appropriate treatment as well as the time frame of treatment options once infection occurs.

Researcher(s)

• Promoter: De Winter Benedicte
• Co-promoter: Malhotra Surbhi
• Co-promoter: Smet Annemieke
• Co-promoter: Verstraeten Aline

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

Irritable bowel syndrome (IBS) is one of the most prevalent gastrointestinal disorders, affecting around 11% of the population. The underlying cause of IBS is still largely unknown. Recently the importance of the immune system and more specifically mast cells (MC) and basophils (BP) was highlighted. These immune cells are heavily influenced by their surroundings and release mediators affecting gut sensitivity in response. In this research project we would like to elucidate the involvement of both mast cells and basophils in the development of IBS, using novel but validated immunological methods, and to study the mediators involved in mast cell and basophil activation in IBS, focusing on the diarrhea-predominant subtype. We will further subdivide these patients according to the underlying cause, concentrating on postinfectious onset and central risk factors (depression and anxiety). First of all, we will study whether BP and cultured MC of IBS patients are immunologically different compared to healthy controls. Subsequently we will study cultured MC in the presence of a large intestinal biopsy extract of IBS patients and healthy controls, to determine whether the gut environment influences MC reactivity. Lastly, we will look at the role of mas-related G protein-coupled receptors (MRGPR), a class of receptors involved in MC activity and in processing of gut pain, as potential therapeutic targets in IBS.

Researcher(s)

• Promoter: De Schepper Heiko
• Co-promoter: De Winter Benedicte
• Co-promoter: Sabato Vito
• Fellow: Van Malderen Kathleen

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

Inflammatory bowel diseases (IBD), colorectal cancer (CRC) and gastric cancer (GC), still remain disease entities with a high morbidity burden and are major contributors to health problems worldwide. The burden of IBD is rising globally with substantial variation in levels and trends of disease. Most available therapies with biologicals are directed against the inflammatory responses, but still a substantial number of patients fail to respond or to obtain full remission. In a later stage, some patients will even need surgery and are facing an increased risk of developing colon cancer. GC and CRC are respectively the third and fourth leading cause of cancer deaths worldwide, as prognosis in the advanced tumour stage still remains poor. While chemotherapy is the cornerstone of cancer therapy, limited efficacy and development of resistance to chemotherapeutic drugs are major challenges in the treatment of these epithelial cancers. Next to this, immunotherapy does not provide major advances in metastatic CRC and GC as the response rate still remains low. One way to improve treatment, is focussing on personalized medicine where efforts must be directed towards the identification of patients who are likely to respond to a specific treatment regimen and optimize its efficacy. This personalization can focus on molecular biomarkers to maximize efficacy and minimize adverse events. Ideally, such biomarkers should have both a prognostic and predictive potential. Assessment of mucosal healing upon therapy is the golden standard to validate treatment efficacy in IBD, but validated markers for disease monitoring have still their limitations. Furthermore, knowledge of the molecular basis of CRC and GC has advanced at a rapid pace in recent years, which led to the identification of potential biomarkers. However, due to the large heterogeneity of these cancer types, such markers are not present in the majority of cancer patients, resulting in restricted efficiency for clinical application. Novel markers that could fit these criteria are the transmembrane MUC1 and MUC13 mucins. Both mucins are highly overexpressed in IBD, CRC and GC patients, making them valuable new markers for clinical implementation. Furthermore, mucins are highly polymorphic and the presence of genetic differences in the MUC1 and MUC13 genes can result in several mRNA isoforms of which some can be implicated in disease. The MUC1 and MUC13 mRNA isoforms associated with IBD, GC and CRC still remain an unexplored conundrum. We have recently performed a proof of concept study in which we identified the MUC1 and MUC13 mRNA isoforms associated with inflammation in IBD. We wish to build upon these data and extend our search to unravel the MUC1 and MUC13 mRNA isoforms as biomarkers to improve follow-up and treatment in IBD, CRC and GC. Therefore, in this project, we will develop and validate a novel biomarker assay, based on MUC1 and MUC13 mRNA isoforms with prognostic and predictive potential, to predict disease outcome and therapy response in IBD, CRC and GC. To do so, we will unravel the MUC1 and MUC13 mRNA isoforms aberrantly expressed in IBD, CRC and GC patients and correlate their expression levels with clinical patient data. Thereafter, we will generate a multiplex RT-qPCR based on a selected isoform panel and validate our assay on tissue and liquid biopsies to evaluate the efficacy of the isoforms as non-invasive prognostic and predictive biomarkers.

Researcher(s)

• Promoter: Smet Annemieke
• Co-promoter: De Winter Benedicte

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

Infection with SARS-CoV-2 mostly leads to a mild self-limiting respiratory tract illness, however, some patients progress to develop severe progressive pneumonia, multiorgan failure, and death. The project aims to determine factors that dictate the severity of COVID-19. Firstly, guided by our prior data of interaction of certain mucins with the ACE2 receptor and the clinical evidence of excessive mucin production in severe COVID-19 illness, we intend to characterize different mucins for their role in both the initiation and progression of COVID-19. Secondly, based on a severe degree of edematous interstitial lung tissue pathology observed in COVID-19 autopsies and its hypothesized link to abnormally low PaO2 observed clinically, the project intends to characterize aquaporin (AQP) water channels that are responsible for fluid transport across cells. This has important therapeutic relevance for COVID-19 as specific AQP inhibitors have been shown to attenuate inflammation and lung injury and to block mucin hypersecretion. Lastly, mucin expression is also a critical factor in microbiome homeostasis and based on, so far, scarce data that co-infection with other respiratory pathogens and other microbial interactions might modulate COVID-19 severity, the project aims to characterize the microbiome associated with different degrees of disease severity. Identifying factors that shape the course of SARS-CoV-2 infection will lead to identification of plausible targets to treat COVID-19.

Researcher(s)

• Promoter: De Winter Benedicte
• Co-promoter: Jorens Philippe
• Co-promoter: Kumar-Singh Samir
• Co-promoter: Malhotra Surbhi
• Co-promoter: Smet Annemieke
• Co-promoter: Verstraeten Aline

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

Irritable bowel syndrome (IBS) is one of the most prevalent gastrointestinal disorders, affecting around 11% of the population. The underlying cause of IBS is still largely unknown. Recently the importance of the immune system and more specifically mast cells (MC) and basophils (BP) was highlighted. These immune cells are heavily influenced by their surroundings and release mediators affecting gut sensitivity in response. In this research project we would like to elucidate the involvement of both mast cells and basophils in the development of IBS, using novel but validated immunological methods, and to study the mediators involved in mast cell and basophil activation in IBS, focusing on the diarrhea-predominant subtype. We will further subdivide these patients according to the underlying cause, concentrating on postinfectious onset and central risk factors (depression and anxiety). First of all, we will study whether BP and cultured MC of IBS patients are immunologically different compared to healthy controls. Subsequently we will study cultured MC in the presence of a large intestinal biopsy extract of IBS patients and healthy controls, to determine whether the gut environment influences MC reactivity. Lastly, we will look at the role of mas-related G protein-coupled receptors (MRGPR), a class of receptors involved in MC activity and in processing of gut pain, as potential therapeutic targets in IBS.

Researcher(s)

• Promoter: De Schepper Heiko
• Co-promoter: De Winter Benedicte
• Co-promoter: Sabato Vito
• Fellow: Van Malderen Kathleen

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

Irritable bowel syndrome (IBS) is a disease without a clear cause which is associated with abdominal pain and altered bowel habits. A disturbed intestinal permeability and an increased sensitivity of internal organs are causal factors of disease. An important pathological role lies in the 'gut-brain interaction' in which signals from the intestine are conveyed to the brain and vice versa. This interaction is essential for a healthy bowel function and involves signaling molecules such as histamine, proteases, bile and fatty acids. Also the microbial content (the 'microbiome') of the intestine plays an important role in the gut-brain interaction. In this respect, we are particularly interested in the intestinal barrier function. The mucous membranes in the intestine provide an active barrier that allows passage of nutrients but impedes non-nutrients and toxins. It is well known that certain chronic diseases are associated with a disturbed intestinal barrier, also called 'leaky gut'. Possibly, a 'leaky gut' is also involved in IBS and that is what we will investigate in this project. We will study the role of different mediators such as vasoactive intestinal polypeptide, intestinal alkaline posphatase, serine protease inhibitors and mucoprotectants in a preclinical rat model and directly translate the importance of these mediators to the human situation validating their occurence and activity in human colonic samples. -

Researcher(s)

• Promoter: De Winter Benedicte
• Co-promoter: De Schepper Heiko
• Co-promoter: Smet Annemieke
• Fellow: Hanning Nikita

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

The serine protease inhibitor UAMC-00050, previously shown efficacious in 2 preclinical IBS models after systemic administration, will be formulated for oral and rectal administration. The drug delivery systems will be tested in the rat IBS model for dose determination, efficacy, time of administration and serum concentrations, a crucial step towards further valorization of the compound.

Researcher(s)

• Promoter: De Winter Benedicte
• Co-promoter: Augustyns Koen
• Co-promoter: Kiekens Filip

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

Gastrointestinal barrier disturbances are postulated to play an important role in the pathogenesis of a wide range of diseases characterised by underlying inflammation and ranging from metabolic disorders (obesity) over gastrointestinal diseases (inflammatory bowel diseases such as Crohn's disease) towards infection (sepsis). 1./ In this translational project we first want to investigate the effect of pharmacological modulation of gastrointestinal barrier dysfunction in three animal models representing different conditions of clinically relevant inflammation; more precisely irritable bowel syndrome (IBS), inflammatory bowel diseases (IBD) and sepsis. The target molecules were chosen based on their proposed role on the epithelial barrier. The role of intestinal alkaline phosphatase, a membrane-bound brush-border enzyme with anti-inflammatory properties, will be investigated on the interplay between intestinal permeability, inflammation and visceral pain. We will also investigate the effect of newly developed serine protease inhibitors on this 'permeability-inflammation-pain' axis because proteases too, being abundantly present both in the gastrointestinal tract and the gastrointestinal lumen, have been proposed as important mediators in permeability, inflammation and visceral pain. 2./ In close parallel with the experimental part and based on the outcome data obtained in our animal models, we will perform a translational study in which human biopsies and/or surgical specimens of patients with IBS, IBD or sepsis will be collected for the validation of the biomarkers identified in the experimental part. The combination of data on the patient's clinical background, his/her immune response and the severity of intestinal permeability disturbances will generate a unique patient profile that might help stratifying patients allowing a personalized treatment. Moreover, as no approved therapeutic agents are currently targeting the epithelial barrier, more research on the gastrointestinal permeability-inflammation-visceral pain axis is eagerly awaited.

Researcher(s)

• Promoter: De Winter Benedicte
• Co-promoter: Jorens Philippe

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

Obstructive sleep apnea (OSA) is characterized by intermittent collapse of the upper airway during sleep resulting in an abnormal sleep pattern and drops in oxygen concentration. It affects up to 50% of children with specific risk factors including obesity and Down syndrome. It results in neurocognitive impairment but can also augment for instance the obesity-related cardiovascular morbidity. Therefore, a correct treatment is mandatory. Adenotonsillectomy, the classical first line treatment, has a success percentage of only 50% or less. This implies that 50% of these children with OSA are at risk of being exposed to unnecessary surgery. The aim of this research project is to identify markers that could predict the outcome of this surgery in children with OSA. In a first study, we will identify markers that correlate with the severity of OSA in these children. More classical markers include for instance body mass index, neck circumference, tonsil size, etc. We will also use a more innovative approach with parameters obtained from CT-scanning and functional imaging methods to describe more detailed physical characteristics of the airway. Second, we will identify markers that predict the success of treatment. Finally, we will introduce an individualized approach by selecting a treatment a priori based on the airway characteristics of a specific patient. We will also use virtual surgery to determine if a specific child will benefit from surgery

Researcher(s)

• Promoter: De Winter Benedicte
• Fellow: Verhulst Stijn

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

IBS affects around 18% of the general population. It is one of the most common disorders seen by physicians. However, the IBS market is commercially weak due to the limited understanding of its pathophysiology and the availability of limited treatment options. In fact, IBS is largely seen as a syndrome rather than a disease. By increasing the understanding of the underlying mechanisms of IBS coupled to validation of therapeutic and diagnostic targets, we have the ambition to turn IBS "from a syndrome into a disease". To achieve this, we want to establish an academic knowledge platform and an industrial network in Flanders that is able to tackle the major challenges in the IBS field, to identify and validate novel therapeutic and diagnostic targets and to develop them into novel therapeutic and diagnostic solutions. When available, this network will put Flanders at the forefront of innovation in the emerging IBS field.

Researcher(s)

• Promoter: Augustyns Koen
• Co-promoter: De Meester Ingrid
• Co-promoter: De Winter Benedicte
• Co-promoter: Lambeir Anne-Marie

Research team(s)

• Medicinal Chemistry (UAMC)

Project type(s)

• Research Project

Abstract

Overweight and obesity in children and adolescents are prevalent, have several long lasting medical and psychosocial comorbidities and post a serious burden on society. Tackling weight problems at an early age in a sustainable way is therefore of utmost importance. Earlier studies of the UGhent and the UZA research groups, showed that in the short term a multidisciplinary obesity treatment (MOT) focusing on behavioral lifestyle approach, has a positive impact on weight and comorbidities. However, existing therapies have only limited success, specifically at long-term. One explanation for these modest results relates to poor executive functions (EFs, e.g., attention, inhibition) in overweight and obesity. EFs are needed for self-control and resisting temptation. The UGhent group investigates since 2011, as the first group worldwide, the potential of EF-training strengthening self-control capacities in obese youth and proved that a computerized EF-training on top of an evidence-based MOT enhances EFs of obese youth, and increases their capability to maintain weight loss until 8 weeks after treatment. This proof-of-concept for the present project is strengthened by recent international studies showing that training individuals to control responses to high-calorie foods via computerized tasks results in weight loss. We aim to show now that adding computerized EF-training to evidence-based MOT further improves weight maintenance until 6-month after MOT and ameliorates medical and psychosocial comorbidities. We will test this in a multicenter longitudinal, prospective randomized RCT. During the regular MOT, 200 obese youngsters (8-18 years) will be randomized on a 1/1 base to either a 6 week EF-training or an active control condition, followed by 8 weekly (training or control) booster sessions. The effects of the EF-training will be measured immediately after the MOT, at 2 month and 6 month. We expect significant effect of EF-training on 1) weight loss maintenance up to 6-months after MOT, 2) EF and 3) comorbidities and related to health benefits. The project partner's extensive professional network and close collaboration with the different partners from the advisory board (BASO, VVK and Eetexpert.be vzw) allows for the broad dissemination of the project results to different target groups. The EF-training (and manual) will be presented to different MOT centers. A train-the-trainer program will be developed. Press releases, communications to the general public and appropriate stakeholders (e.g., health authorities, medical societies and youth health organizations) and scientific presentations and publications will report on the project's activities and results.

Researcher(s)

• Promoter: De Winter Benedicte
• Co-promoter: Verhulst Stijn

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

The Infla-Med consortium performs fundamental research on the pathophysiological processes of inflammatory diseases (cardiovascular, gastrointestinal, renal and infectious disease) by using a multidisciplinary approach (pathophysiology, pharmacology, biochemistry and medicinal chemistry). The consortium is embedded within the research priorities 'Drug Research' and 'Infectious Diseases' of the University of Antwerp. Recently, the University of Antwerp assigned the Infla-Med consortium as Research Consortium of Excellence.

Researcher(s)

• Promoter: De Meyer Guido
• Co-promoter: Augustyns Koen
• Co-promoter: De Meester Ingrid
• Co-promoter: De Winter Benedicte
• Co-promoter: D'Haese Patrick
• Co-promoter: Lambeir Anne-Marie
• Co-promoter: Maes Louis
• Co-promoter: Vrints Christiaan

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

This project will (1) investigate the importance of the gastrointestinal tract as initiator and maintainer of sepsis by correlating the immune response in the GI tissue to the systemic immune response, (2) evaluate the interaction between immune cells and the neuronal system thereby increasing our knowledge in the field of neuroimmune modulation and (3) specifically looking into DC- and T cell-targeted therapies for the treatment of sepsis ultimately leading to novel strategies to treat critically ill patients.

Researcher(s)

• Promoter: De Winter Benedicte
• Co-promoter: Jorens Philippe

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

Visceral hypersensitivity and altered intestinal permeability are common key features of two major gastrointestinal disorders, inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). Alterations in the density of mucosal cells, such as enterochromaffin cells and mast cells, and in their activation status and mediator release (serotonin and proteases) have been described in IBS and IBD patients. Our first aim is to investigate whether these mediators can induce visceral hypersensitivity directly by activating the afferent nerve endings in the gut wall or indirectly via modulation of the intestinal barrier function. Increased permeability of the intestinal barrier facilitates the entrance of antigens, activating immune cells and other cell types in close proximity to afferent nerves. Therefore we will use an experimental model for postinflammatory visceral hypersensitivity that is routinely used in our lab and is based on a rat model of TNBS colitis. Visceral hypersensitivity and intestinal permeability will be extensively studied using a combination of validated in vivo and in vitro techniques: the in vivo visceromotor response and in vitro afferent neuronal activity to colonic distension (both indicators of visceral hypersensitivity) next to the Evans blue permeability method, all of which routinely used in our lab. In the first work package (WP1), the effect of pharmacological agents interfering with serotonin (5-HT) 2B and 5-HT4 receptors or with the serotonin synthesis will be assessed on visceral sensitivity and intestinal permeability. In WP2, newly developed potent protease inhibitors reducing tryptase and matriptase activity (in collaboration with ADDN) will be tested to define the contribution of these proteases to visceral sensitivity and intestinal barrier function. These two work packages will allows us to gain further insight in the incompletely elucidated pathophysiology underlying visceral hypersensitivity and impaired barrier function and to identify new drug targets for the treatment of IBS. The second aim of the project (WP3) is to validate the role of these serotonergic targets and proteases in a translational set-up using colonic biopsies from patients with IBS and quiescent IBD. The effect of the supernatant derived from these biopsies will be investigated on afferent neuronal signalling in the presence or absence of specific inhibitors identified in WP1 and WP2 to confirm their relevance in a clinically relevant context.

Researcher(s)

• Promoter: De Winter Benedicte
• Fellow: Ceuleers Hannah

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project website

Project type(s)

• Research Project

Abstract

In the current project, we initially aim to identify the different neuroimmune players and their interactions in the gastrointestinal tract during septic ileus. Afterwards, we seek to modulate the interactions between neurons and inflammatory cells at the neuronal level or via immune modulation.

Researcher(s)

• Promoter: De Winter Benedicte
• Co-promoter: Pelckmans Paul
• Fellow: Nullens Sara

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

The aim of this study is to address the role of and the interactions between mast cells, afferent neurons and enterochromaffin cells (ECC) in the development of colonic hypersensitivity and disturbed gastrointestinal reflexes in a postinflammatory rat model.

Researcher(s)

• Promoter: De Winter Benedicte
• Co-promoter: Pelckmans Paul

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

Dendritic cells (DCs) are central mediators that keep the balance between immunity to foreign antigens and immune tolerance to self-proteins. Disruption of this balance may lead to disease. We aim to unravel the role of DCs in T-helper (Th)1/Th17-mediated immune diseases (including inflammatory bowel disease, multiple sclerosis, cardiovascular disease and rheumatoid arthritis), with the purpose to design novel DC-targeted therapeutic strategies.

Researcher(s)

• Promoter: Vrints Christiaan
• Co-promoter: Berneman Zwi
• Co-promoter: De Winter Benedicte
• Co-promoter: Ebo Didier
• Co-promoter: Schrijvers Dorien

Research team(s)

Project type(s)

• Research Project

Abstract

The aim of this research project is to identify markers that could predict the outcome of this surgery in obese children with OSA. In a first study, we will identify markers that correlate with the severity of OSA in these children. More classical markers include for instance body mass index, neck circumference, tonsil size, etc. We will also use a more innovative approach with parameters obtained from CT-scanning and functional imaging methods to describe more detailed physical characteristics of the airway. Second, we will identify markers that predict the success of treatment. Finally, we will introduce an individualized approach by selecting a treatment a priori based on the airway characteristics of a specific patient. We will also use virtual surgery to determine if a specific child will benefit from surgery.

Researcher(s)

• Promoter: De Winter Benedicte
• Fellow: Verhulst Stijn

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

In the current project, we initially aim to identify the different neuroimmune players and their interactions in the gastrointestinal tract during septic ileus. Afterwards, we seek to modulate the interactions between neurons and inflammatory cells at the neuronal level or via immune modulation.

Researcher(s)

• Promoter: De Winter Benedicte
• Co-promoter: Pelckmans Paul
• Fellow: Nullens Sara

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

Inflammatory bowel disease (IBD) is a gastrointestinal disease of unknown aetiology that is characterized by episodes of acute bowel inflammation alternating with phases of remission during which inflammation fades away. IBD in remission is interrelated with irritable bowel syndrome (IBS), which is 'functional' gastrointestinal disorder. IBD in remission and IBS both occur in the absence of obvious structural bowel abnormalities and patients suffer from comparable symptoms such as abdominal pain, diarrhoea, constipation and weight loss. These symptoms affect the patient's quality of life considerably, especially because treatment is often difficult and clinically challenging. The bowel contains sensory nerves which transmit signals within the intestinal wall and to the brain. These signals regulate vital bowel functions such as gastric emptying and food propulsion but also nausea and pain. Recent evidence suggests that sensory nerves in patients with IBS and IBD in remission are hypersensitive, leading to uncontrolled nerve signalling and disturbed motility. A better insight of sensory nerve signals and the molecules that modulate them, will lead to better treatment options of functional complaints in patients with IBS and IBD in remission. This will improve their quality of life leading to more efficient medical consumption and to a reduced socio-economic burden.

Researcher(s)

• Promoter: De Winter Benedicte
• Co-promoter: Moreels Tom
• Co-promoter: Pelckmans Paul
• Fellow: Deiteren Annemie

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

Inflammatory bowel disease (IBD) is a gastrointestinal disease of unknown aetiology that is characterized by episodes of acute bowel inflammation alternating with phases of remission during which inflammation fades away. IBD in remission is interrelated with irritable bowel syndrome (IBS), which is 'functional' gastrointestinal disorder. IBD in remission and IBS both occur in the absence of obvious structural bowel abnormalities and patients suffer from comparable symptoms such as abdominal pain, diarrhoea, constipation and weight loss. These symptoms affect the patient's quality of life considerably, especially because treatment is often difficult and clinically challenging. The bowel contains sensory nerves which transmit signals within the intestinal wall and to the brain. These signals regulate vital bowel functions such as gastric emptying and food propulsion but also nausea and pain. Recent evidence suggests that sensory nerves in patients with IBS and IBD in remission are hypersensitive, leading to uncontrolled nerve signalling and disturbed motility. A better insight of sensory nerve signals and the molecules that modulate them, will lead to better treatment options of functional complaints in patients with IBS and IBD in remission. This will improve their quality of life leading to more efficient medical consumption and to a reduced socio-economic burden.

Researcher(s)

• Promoter: De Winter Benedicte
• Co-promoter: De Man Joris
• Co-promoter: Moreels Tom
• Co-promoter: Pelckmans Paul
• Fellow: Deiteren Annemie

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

This project represents research between the UA and a private institution. UA provides the private institution the research results named in the title of the project.

Researcher(s)

• Promoter: Pelckmans Paul
• Co-promoter: De Winter Benedicte
• Fellow: Wyndaele Michel

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

The aim of this project is to study the effect of experimental rat colitis in the postinflammatory phase (remission) on the motility of the gastrointestinal tract and the sensitivity of afferent nerves innervating the colon. We will study the pathophysiology of the postinflammatory motility- and sensitivity disturbances by investigating the involvement of TRPV1 and P2X3 receptors, mast cells and serotonin-containing enterochromaffin cells.

Researcher(s)

• Promoter: Pelckmans Paul
• Co-promoter: De Winter Benedicte

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Pelckmans Paul
• Co-promoter: De Wachter Stefan
• Co-promoter: De Winter Benedicte
• Fellow: Wyndaele Michel

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

In this study we want to investigate whether gastrointestinal afferent neurons are involved in the pathogenesis of postinflammatory motility and sensitivity disorders following recovery from TNBS colitis in rats. Furthermore, the pathogenic role of different mediators in the sensitization of these afferent neurones will be examined amongst others using electrophysiological techniques.

Researcher(s)

• Promoter: De Winter Benedicte

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

Helminths posses immune modulating capacities that can be used for the treatment of immunological diseases like IBD. This new therapeutic modality was shown to be successful with living worms. However, the use of living parasites is critisised because of potential dangers. Therefore, we want to investigate whether non-infectious worm-derived antigens can also be used in the prevention and treatment of experimental gastrointestinal inflammation and the related sensorimotor disturbances. The underlying immunological mechanisms are studied by means of histological, biochemical and molecular biology techniques. Sensorimotor disturbances are studied both in vivo and in vitro.

Researcher(s)

• Promoter: Pelckmans Paul
• Co-promoter: De Winter Benedicte
• Co-promoter: Moreels Tom

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

Crohn's disease is a chronic inflammatory disease of which the pathogenic stimulus is yet unknown. The aim of the present study is to investigate the preventive and/or therapeutic effect of administration of helminth antigens of Schistosoma mansoni and Ancylostoma caninum on experimentally-induced colitis in mice. The effect of helminth antigens and the underlying immunological mechanisms will be studied on the degree of colitis and the colitis-associated gastrointestinal motility disturbances.

Researcher(s)

• Promoter: De Winter Benedicte

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

Introduction: Inflammation of the gastrointestinal tract can lead to disturbed motility and symptoms such as nausea, dyspepsia and diarrhea. After the gastrointestinal inflammation subsides, these bowel problems persist in one third of patients. A role for the enteric nervous system and afferent nerves was suggested. Aims: To determine the role of afferent neurones in the pathogenesis of gastrointestinal motility disturbances caused by TNBS-induced colitis in the rat, using functional and histological techniques. Methods: In vitro contractility experiments on isolated muscle strips and peristalsis measurements on bowel segments will be combined with in vivo assessment of gastric emptying and intestinal transit. A new technique will be introduced for direct measurement of afferent nerve discharge. Histological evaluation will complement these functional studies using routine and c-fos staining). Planning: In a first period, the role of synaptic neurotransmission and of extrinsic afferent neurones will be determined in vivo and in vitro. A second period will concentrate on the role of inflammatory mediators. Finally, the inflammatory modulation of receptor expression on afferent neurones will be studied.

Researcher(s)

• Promoter: Pelckmans Paul
• Co-promoter: De Winter Benedicte
• Fellow: De Schepper Heiko

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

Inflammation of the gastrointestinal tract such as in Crohn's disease is associated with gastrointestinal motility disturbances. The pathogenesis of these motility disturbances are largely unknown but a role for afferent neurons is suggested. Therefore, the aim of the present project is to study in detail afferent nerve function during TNBS-induced inflammation of the rat gastrointestinal tract and to study the neurotransmitters, receptors and mediators involved in these changes.

Researcher(s)

• Promoter: De Winter Benedicte

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

It awaits to be revealed which stimuli and which conditions in the gastrointestinal tract result in a disturbed afferent nerve function. Therefore, the aim of the present project is to study afferent nerve function during inflammation of the gastrointestinal tract and to study the neurotransmitters and receptors that are involved in these changes. In rats with trinitrobenzene sulphonic acid (TNBS)-induced colitis and in mice with lipopolysaccharides (LPS)-induced sepsis, we will study in detail whether the interaction between gastrointestinal inflammation and gastrointestinal motility is co-ordinated by afferent nerve signalling and which mediators are capable of altering the afferent nerve activity. The functional studies will be performed in the laboratory of Gastroenterology (Prof. Pelckmans, University of Antwerp, Faculty of Medicine) and the histological studies will be performed in the laboratory of Cell Biology and Histology (Prof. Timmermans, University of Antwerp, Facultyof Biomedical Sciences).

Researcher(s)

• Promoter: Pelckmans Paul
• Co-promoter: De Winter Benedicte

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

The effect of inflammation on the regulation of gut motility is studied in several experimental models such as rat jejunitis, rabbit colitis and on mice infected with Schistosoma mansoni. Special attention is paid to disturbances of the inhibitory nitrergic innervation, and of smooth muscle function in particular the modulation of motilin and substance P receptors.

Researcher(s)

• Promoter: De Winter Benedicte
• Promoter: Pelckmans Paul

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

Postoperative ileus is a major medical complication of which the pathogenesis is unknown. We hypothesize that ileus might be caused by an hyperactivity of the non-adrenergic non-cholinergic neurons (NANC) releasing nitric oxide as their neurotransmitter. We investigate this hypothesis by in vitro and in vivo experiments in rats.

Researcher(s)

• Promoter: Pelckmans Paul
• Fellow: De Winter Benedicte

Research team(s)

Project type(s)

• Research Project

Abstract

Postoperative ileus is a major medical complication of which the pathogenesis is unknown. We hypothesize that ileus might be caused by an hyperactivity of the non-adrenergic non-cholinergic neurons (NANC) releasing nitric oxide as their neurotransmitter. We investigate this hypothesis by in vitro and in vivo experiments in rats.

Researcher(s)

• Promoter: Pelckmans Paul
• Fellow: De Winter Benedicte

Research team(s)

Project type(s)

• Research Project