Research Bart Loeys

Abstract

Impaired TGFß signaling is a defining feature of thoracic aortic aneurysm and dissection (TAAD) related disorders, such as Loeys-Dietz syndrome. While pathogenic variants affecting TGFß signaling components are known to underlie these conditions, the precise mechanisms through which these specific variants induce pathology are not fully understood. While vascular smooth muscle cell (VSMC) dysfunction is often implicated due to medial degeneration, endothelial cells (ECs) have been overlooked in this context. Dysregulated endothelial nitric oxide (NO) signaling has been linked to aneurysm development, yet its connection to TGFß signaling remains unclear. This project aims to unravel the TGFß paradox and explore how impaired TGFß signaling impacts NO regulation using in vivo fluorescent light sheet imaging in zebrafish. By employing a unique fluorescent TGFß reporter specific to ECs and VSMCs, we will observe real-time TGFß signaling dynamics in a zebrafish Tgfb2 knockout model. Subsequently, utilizing a novel genetically encoded endothelial NO probe (geNOps), we will investigate the influence of impaired TGFß signaling on NO regulation through in vivo imaging. Finally, we will identify therapeutic targets using a single-cell RNA sequencing approach on the novel zebrafish model we developed. This will bring us closer to a curative therapy for life-threatening TAAD and pave the way for the identification of prognostic biomarkers of aortic disease severity.

Researcher(s)

• Promoter: Loeys Bart
• Co-promoter: Schepers Dorien
• Fellow: Verbiest Justine

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

Thoracic aortic aneurysms (TAAs) predispose to aortic dissection or rupture, a catastrophic event associated with an ultimate mortality rate of 80% and, hence, a prominent cause of morbidity and mortality in the Western population. If TAA is detected timely, prophylactic surgery can drastically reduce mortality rates but comes with a significant risk of complications. As there are currently no medical therapies capable of stopping or even reversing TAA formation, there is a high need for such medications. Although much progress has been made in our understanding of some mechanisms underlying TAA, we lack deep insight at the single cell resolution. The latter is essential if we want to develop more efficient drugs. Within this project we take advantage of the genetic knowledge of Marfan syndrome, a defined monogenic model for TAA development, and its related but opposing fibrillinopathies, stiff skin syndrome and acromelic dysplasia. These two conditions are also caused by pathogenic variants in FBN1 (gene coding for fibrillin-1) but do not present aortic aneurysm development. By studying the aorta in their respective mouse models at a single cell resolution, we aim to identify novel therapeutic targets which we will then test and validate in our already created iPSC derived cell models of these conditions. The anticipated findings will advance the pathomechanistic TAA knowledge beyond the current understanding and will pave the way for novel therapeutic strategies.

Researcher(s)

• Promoter: Loeys Bart
• Co-promoter: Peeters Silke

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

Progressive dilatation of the thoracic aorta leads to the development of thoracic aortic aneurysms (TAAs), which are often asymptomatic but predispose to dissection and rupture. The latter are associated with high mortality rates. Even though over 40 TAA genes have been identified in the past, the cause remains elusive for the majority of patients (70% of familial and 85-90% of sporadic patients), despite exhaustive Mendelian whole exome sequencing efforts for both single nucleotide variants and copy number variant detection of the coding exons of these TAA genes. Moreover, all recently identified genes each only explain very small proportions (<1%) of previously genetically elusive TAA patients. Hence, there is a need to explore novel avenues that move beyond these traditional approaches. Various types of previously un(der)explored genetic variants may explain the missing TAA heritability. In this project, I will therefore determine (1) which proportion of sporadic TAA patients can genetically be explained by the presence of somatic mutation in affected aortic tissue using deep whole exome sequencing and (2) what is the role of (non-coding) structural variants in the development of TAA using short- and long-read whole genome sequencing.

Researcher(s)

• Promoter: Loeys Bart
• Fellow: Meester Josephina

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

Pathogenic variants in biglycan cause two divergent phenotypes: Meester-Loeys syndrome (MRLS) and X-linked spondyloepimetaphyseal dysplasia (SEMDX). The latter is characterized by a disproportionate short stature and caused by missense variants. MRLS, on the other hand, is a syndromic form of thoracic aortic aneurysm that is caused by loss-of-function variants. Intriguingly, MRLS patients with partial biglycan deletions present with a more severe skeletal phenotype. To date, discriminative pathomechanisms explaining why certain biglycan mutations cause MRLS and others SEMDX remain elusive. This PhD project aims to answer this research question using induced pluripotent stem cells (iPSCs) of both patient groups and their respective (isogenic) controls. IPSC-based disease modeling provides a unique opportunity for pathomechanistic investigation in a patient-, variant- and cell type-specific manner. After the creation of disease-relevant patient-derived iPSC-vascular smooth muscle cells and -chondrocytes, I will identify cell type-specific differences between MRLS and SEMDX using (1) functional assays tailored to existing pathomechanistic insights, and (2) hypothesis-free transcriptomic and proteomic approaches. Finally, I will investigate the mutational effect of partial biglycan deletions to establish a specific MRLS genotype-phenotype association.

Researcher(s)

• Promoter: Loeys Bart
• Co-promoter: Meester Josephina
• Co-promoter: Verstraeten Aline
• Fellow: Hebert Anne

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

Thoracic aortic aneurysm (TAA) denotes a progressive enlargement of the thoracic aorta, entailing a significant risk for life-threatening aortic dissection and/or rupture. At present, mouse models are often used to investigate and therapeutically target the molecular defects underlying TAA, as native aortic samples of patients and, especially, control individuals are hard to collect. Yet, murine in vivo studies are often lengthy and drug testing results did previously not always recapitulate in patients. With the advent of induced pluripotent stem cells (iPSCs), the field is closing in on apt solutions to faithfully model patient and control aortas in a dish. The currently available vascular smooth muscle cell (VSMC) or endothelial cell (EC) monocultures are still overly simplified, as they fail to adequately replicate the complex multilayered and multicellular structure of the aorta. Taking advantage of available iPSCs from syndromic TAA patients (FBN1 & IPO8), my project aims to 1) develop and consolidate the validity of the first iPSC-derived TAA aorta-on-a-chip models, comprising the two VSMC subtypes populating the native ascending aorta along with a layer of arterial ECs, and 2) use the established model to further investigate the disease mechanisms underlying the relatively unexplored IPO8 syndrome. The anticipated outcomes will contribute to the replacement of mouse models (3R principle) and expedite pathophysiological TAA research and drug discovery.

Researcher(s)

• Promoter: Verstraeten Aline
• Co-promoter: Loeys Bart
• Fellow: Fedoryshchenko Ivanna

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

Thoracic aortic aneurysm (TAA) denotes a progressive enlargement of our body's largest artery, i.e. the aorta. It frequently remains unnoticed until aortic dissection and/or rupture occur, which are associated with high mortality rates. Although prophylactic aortic surgery can serve as a lifesaving event, it comes with important risks. Current drug therapies can only slow down TAA progression to some extent, but cannot fully prevent aortic dissections/ruptures. Better therapeutic options are clearly needed. TAA and the ensuing aortic complications are a hallmark of a rare connective tissue disorder, called Loeys-Dietz syndrome (LDS). While LDS-related TAA is relatively understudied as compared to other TAA conditions, it is an important study case considering its early onset and aggressive disease course. Taking advantage of the advent of the iPSC technology and our expertise in clinical and pathophysiological LDS research as well as iPSC-vascular smooth muscle cell and iPSC-endothelial cell disease modelling, we want to significantly expedite bench-to bedside translation of LDS research by developing and functionally validating iPSC-derived aorta-on-a-chip (AoC) models of TAA-presenting patients and isogenic controls. Upon demonstration of the known pathomechanisms and drug responses in SMAD3 mutant AoCs, we will investigate if our AoC models can also recapitulate between-patient variability in disease severity. In conclusion, we here take up the challenge to develop a novel pre-clinical tool allowing exploration and therapeutic targeting of LDS mechanisms in a human setting that more closely resembles the native aorta than ever before. The anticipated results will prove relevant for TAA in general, as the AoC expertise that will be acquired within the frame of this project can immediately be translated to other TAA conditions.

Researcher(s)

• Promoter: Verstraeten Aline
• Co-promoter: Loeys Bart
• Fellow: Bousbaa Amira

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

Bicuspid aortic valve (BAV) is the most common congenital heart defect, affecting 1-2% of the general population. This aortic valve defect, which has a male predominance (3:1), is characterized by two semilunar leaflets instead of the normal three. BAV usually remains unnoticed, until patients develop clinical complications such as valvular dysfunction and/or thoracic aortic aneurysm (TAA, 20-30%). TAA is a pathological widening of the aorta in the thorax caused by vascular wall weakness, entailing a high risk for acute dissection and/or rupture (mortality rates ≥70%). Over the past decades, extensive gene discovery efforts have identified about 30 BAV/TAA-associated genes, explaining less than 6% of the BAV-related aortopathy patients. Their identification, and functional characterisation, have been key steps in acquiring our current molecular knowledge on this disease. Though, the still incomplete pathogenic picture hampers the identification of individuals at-risk for TAA, and the discovery of novel therapeutic targets to prevent and/or stop TAA formation. Our research group identified the SMAD6 gene as a novel cause for BAV/TAA disease, which accounts for 4.8% of the 6% genetically solved BAV-related aortopathy patients. More recently, I developed a Smad6 knockout mouse model mimicking human BAV-related aortopathy. In this project, I aim to identify disease-associated genes by using the transcriptomic profiling of Smad6-deficient mice with a highly penetrant outflow tract phenotype in order to prioritize, and strengthen the genetic link of novel and candidate genes with BAV-related aortopathy in humans. The project's anticipated outcomes will advance our current understanding on the molecular basis of the most important known genetic factor implicated in human BAV-related aortopathy.

Researcher(s)

• Promoter: Loeys Bart
• Co-promoter: Luyckx Ilse

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

Thoracic aortic aneurysm (TAA) is an abnormal widening of the aorta in the chest, caused by the weakening of the aortic wall. TAAs can lead to rupture or dissection, a devastating complication with a mortality rate of 50%. Despite considerable efforts to gain insights on the molecular mechanisms underlying TAAs, there is currently no therapy that effectively stops or reverses TAA development. Single-cell RNA sequencing (scRNA-seq) is emerging as a ground-breaking technology to investigate gene expression at single-cell level and is opening new avenues to discover yet unexplored disease pathways. In my project, I will apply this technique to investigate a novel TAA disorder caused by bi-allelic pathogenic variants in the IPO8 gene, recently discovered in our Cardiogenomics research group. I will search for differentially expressed genes (DEGs) within the different aortic cell populations from an Ipo8-/- mouse model that recapitulates the human aortic aneurysmal phenotype. I will also investigate shared DEGs between Ipo8-/- mice and additional TAAs mouse models to find convergent disease pathways in clinically related TAA disorders. Subsequently, I will validate the role of the identified candidate culprits in mouse TAA development in a human setting, by using CRISPR-inhibition or -activation in iPSCs derived vascular smooth muscle cells or endothelial cells. The predicted outcomes will potentially pinpoint novel TAA drivers and hence, unveil potential new therapeutic targets.

Researcher(s)

• Promoter: Verstraeten Aline
• Co-promoter: Loeys Bart
• Co-promoter: Meester Josephina
• Fellow: Valdivia Callejon Irene

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

Over the last decade, four interfaculty research groups of the Center for Medical Genetics of the University of Antwerp have contributed significantly to the genetic underpinning of a wide range of heritable disorders. In the current project these groups will address two fundamental challenges: first, how can we better understand and predict the biological consequences of coding and non-coding variation in the human genome and second, how can we translate this understanding in new treatment strategies. In order to address these challenges we will apply state-of-the-art technology, including whole genome sequencing, long read sequencing (in collaboration with VIB), methylomics, single cell RNAseq and gene editing (CRISPR/Cas) into robust models systems such as advanced mouse and zebrafish models as well as induced pluripotent stem cells (iPSC) and Human Embryonic Stem Cells (hESCs). The four research groups have an established network with clinicians and industry to transfer genetic knowledge into biomarkers and to translate the new genetic insights into innovative therapies.

Researcher(s)

• Promoter: Loeys Bart

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

Thoracic aortic aneurysm (TAA) is an abnormal widening of the thoracic aorta caused by blood vessel wall weakness. TAAs entail a high risk for aortic rupture or dissection, commonly leading to sudden death. To date, genetic defects in >35 genes have been linked with TAA, providing a molecular cause for about 30% of patients. Their identification and functional characterization have been key in acquiring our current pathomechanistic aortopathy knowledge. Yet, the genetic and mechanistic picture for TAA is far from complete, hampering identification of predictive markers for aneurysm formation and development of therapies capable of stopping or reversing aneurysm formation. In search for novel TAA genes, our research group most recently identified recessive truncating IPO8 mutations as a novel cause of syndromic TAA. This project builds on this exciting finding, remarkable Ipo8-/- mouse background differences and the availability of IPO8 mutant iPSCs and isogenic controls. More specifically, we aim to significantly improve our current pathomechanistic insight in TAA caused by IPO8 deficiency based on 1) transcriptomics to unravel the involved biological pathways; and 2) identification of proteins and miRNAs with an abnormal cytosol/nucleus distribution upon IPO8 depletion. In the long term, this project's anticipated results will identify new targets for drug therapies, improving TAA patient management.

Researcher(s)

• Promoter: Loeys Bart
• Co-promoter: Meester Josephina
• Co-promoter: Verstraeten Aline
• Fellow: Buccioli Lucia

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

Impaired TGF-ß signaling has been implied in thoracic aortic aneurysm and dissection (TAAD) related disorders such as Loeys-Dietz syndrome. Although pathogenic variants in genes coding for components of the TGF-ß signaling pathway have been identified as causal for these diseases, the precise mechanisms by which these specific variants lead to pathology remain elusive. Since medial degeneration is the main pathological substrate for TAAD, vascular smooth muscle cell (VSMC) dysfunction is often considered as the main culprit, but the role of endothelial cells (ECs) is neglected. Dysregulated endothelial nitric oxide (NO) signaling contributes to aneurysm development, but its link to TGF-ß signaling remains vague. With this project, I will elucidate the TGF-ß paradox and investigate the effect of impaired TGF-ß signaling on NO regulation by in vivo fluorescent light sheet imaging in zebrafish. I will use an innovative EC and VSMC specific fluorescent TGF-ß reporter to study TGF-ß signaling in real time in a zebrafish Tgfb2 knockout line. Next, by using a novel genetically encoded eNO probe (geNOps), I will investigate how impaired TGF-ß signaling affects NO regulation by in vivo imaging. Finally, I will identify therapeutic targets using an RNA sequencing approach on the novel zebrafish models I developed. This will bring us closer to a curative therapy for life-threatening TAAD and pave the way for the identification of prognostic biomarkers of aortic disease severity.

Researcher(s)

• Promoter: Loeys Bart
• Fellow: Schepers Dorien

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

The aorta is the body's main artery and supplies oxygenated blood to all parts of the body. Progressive dilatation of the aorta leads to the development of thoracic aortic aneurysms and dissections (TAADs), which are often asymptomatic but predispose to aortic dissection and rupture. The latter are associated with high mortality rates. In 2017, I identified mutations in BGN (Biglycan), an X-linked gene, as a novel cause of a severe syndromic form of TAAD, which shows clear clinical overlap with Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS), and is now designated as Meester-Loeys syndrome (MRLS). Based on the current knowledge, it remains unknown which molecular mechanisms explains how loss-of-function mutations in BGN lead to syndromic TAAD (MRLS). Within this project, I aim to further unravel the pathomechanism underlying MRLS using (single cell) transcriptomic approaches in an in vivo BALB/cA Bgn KO mouse model and validate these findings in an in vitro human iPSC-VSMC model. The expected results will be beneficial for genetic counselling and clinical follow-up of the families. Furthermore, they can lead to the development of more personalized preventive therapeutic strategies. In the long run, I anticipate that our research group will also use these mouse and cell models for drug compound screenings for syndromic TAAD.

Researcher(s)

• Promoter: Meester Josephina
• Co-promoter: Loeys Bart

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

The Vevo LAZR-X is an imaging platform for preclinical applications capable of acquiring in vivo anatomical, functional and molecular data. It combines ultra high frequency ultrasound with photoacoustic imaging (a new biomedical imaging modality based on the use of lasergenerated ultrasound) for high resolution images as well as software for analysis and quantification. This equipment will be used in the context of the study of (cardio)vascular diseases, genetics of the heart, heart valves and aortic dissection, kidney diseases and their effects on the heart and blood vessels, and for cancer research.

Researcher(s)

• Promoter: De Meyer Guido
• Co-promoter: De Keulenaer Gilles
• Co-promoter: Heidbuchel Hein
• Co-promoter: Loeys Bart
• Co-promoter: Smits Evelien
• Co-promoter: Van Craenenbroeck Emeline
• Co-promoter: Verhulst Anja
• Co-promoter: Verstraeten Aline

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Marfan syndrome (MFS) and acromelic dysplasias (AD) are caused by pathogenic variants in the fibrillin-1 (FBN1) gene. Remarkably, whereas MFS is characterized by aortic aneurysms and dissections, tall stature and arachnodactyly, AD patients present with short stature, brachydactyly, and no aortic involvement. To date, the divergent pathophysiological mechanisms explaining these contrasting phenotypes remain largely unknown. Loss of structural integrity of the microfibrils is proposed as the cause of MFS, while altered protein-protein interactions to the TB5 domain of FBN1 are thought to be at heart of the pathogenesis of AD. However, the alterations in protein interactions identified so far do not seem to fully explain the AD phenotype. Remarkably, increased transforming growth factor beta (TGF-β) signaling has been considered both in human and murine MFS aortic wall tissue and in fibroblasts of AD patients. As such, the exact functional consequences of the AD and MFS mutations on cell signaling pathways remain a matter of debate to date. The main questions remain: (1) why aortic disease is unique to MFS and (2) what is the exact role of the TB5 domain of FBN1? In this project, I want to decipher the pathomechanistic processes underlying these distinct aortic phenotypes by applying multi-omics approaches in murine and human (cellular) models of MFS and AD. The expected results may reveal novel (preventive) therapeutic targets, which is important to treat the life-threatening aortic aneurysms from which MFS patients are suffering.

Researcher(s)

• Promoter: Loeys Bart
• Co-promoter: Peeters Silke

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

Marfan syndrome (MFS) and acromelic dysplasias (AD) are caused by pathogenic variants in the fibrillin-1 (FBN1) gene. Remarkably, whereas MFS is characterized by thoracic aortic aneurysms (TAA), tall stature and arachnodactyly, AD patients present with short stature, brachydactyly, and no aortic involvement. Loss of structural integrity of the microfibrils is proposed as the cause of MFS, while altered protein interactions are thought to be at heart of the pathogenesis of AD. However, the alterations in protein interactions identified so far do not seem to fully explain the AD phenotype. Remarkably, increased transforming growth factor beta (TGF-?) signaling has been observed both in human and murine MFS aortic wall tissue and in fibroblasts of AD patients. As such, the exact functional consequences of AD and MFS mutations on cell signaling pathways remain a matter of debate. The main questions therefore remain: (1) which mechanisms explain why TAA is unique to MFS? And (2) why do heterozygous FBN1 mutations, both leading to increased TGF-? signaling, give rise to opposite skeletal phenotypes? In this project, I want to decipher the divergent pathomechanistic processes underlying these contrasting skeletal and aortic phenotypes by applying multi-omics approaches in murine and human (cellular) models of MFS and AD. The expected results may reveal novel therapeutic targets, which is especially important to treat the life-threatening TAA from which MFS patients are suffering.

Researcher(s)

• Promoter: Loeys Bart
• Co-promoter: Mortier Geert
• Fellow: Peeters Silke

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

Progressive dilatation of the aorta leads to the development of thoracic aortic aneurysms (TAAs), frequently resulting in aortic dissection or rupture. The latter events associate with an ultimate mortality rate of 50% and, hence, represent a prominent cause of morbidity and mortality in the Western population. Prophylactic surgery of TAA patients reduces the mortality rate down to about 5%, but comes with a relatively high risk of complications. Medical therapies capable of stopping or even reversing aneurysm formation are clearly highly needed, but are not available yet. Further deciphering of the mechanisms underlying TAA is essential to develop more efficient drugs. Owing to the advent of -omics technologies, it is now possible to dig into pan-TAA pathomechanisms in a hypothesis-free manner, opening new avenues to discover yet unexplored disease pathways and, hence, novel therapeutic targets. With this project, we want to be the first to take up the challenge of discovering convergent disease-linked pathways for TAA in a hypothesis-free manner using mouse and iPSC-derived cell models. The anticipated findings will advance the pathomechanistic TAA knowledge significantly beyond the current understanding and will greatly facilitate the development of novel therapeutic strategies.

Researcher(s)

• Promoter: Loeys Bart
• Co-promoter: Verstraeten Aline

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

Precision medicine is an approach to tailor healthcare individually, on the basis of the genes, lifestyle and environment of an individual. It is based on technologies that allow clinicians to predict more accurately which treatment and prevention strategies for a given disease will work in which group of affected individuals. Key drivers for precision medicine are advances in technology, such as the next generation sequencing technology in genomics, the increasing availability of health data and the growth of data sciences and artificial intelligence. In these domains, 6 strong research teams of the UAntwerpen are now joining forces to translate their research and offer a technology platform for precision medicine (PreMeT) towards industry, hospitals, research institutes and society. The mission of PreMeT is to enable precision medicine through an integrated approach of genomics and big data analysis.

Researcher(s)

• Promoter: Laukens Kris
• Co-promoter: Bittremieux Wout
• Co-promoter: Kooy Frank
• Co-promoter: Loeys Bart
• Co-promoter: Meester Josephina
• Co-promoter: Meysman Pieter
• Co-promoter: Mortier Geert
• Co-promoter: Op de Beeck Ken
• Co-promoter: Van Camp Guy
• Co-promoter: Van Hul Wim
• Co-promoter: Verstraeten Aline
• Fellow: Bosschaerts Tom
• Fellow: Gauglitz Julia

Research team(s)

• ADReM Data Lab (ADReM)

Project type(s)

• Research Project

Abstract

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with pleiotropic ocular, skeletal and cardiovascular manifestations. Morbidity and mortality are mostly determined by aortic root aneurysm, dissection and rupture. Although mutations in FBN1, coding for fibrillin-1, are the sole genetic MFS cause, there is a poor correlation between the MFS phenotype and the nature or location of the FBN1 variant. Wide intra- and interfamilial phenotypic variability, ranging from completely asymptomatic to sudden death at young age, is observed. The precise mechanisms underlying this variability remain elusive. In this project, we have selected an innovative strategy to fully understand the functional effects of the FBN1 mutation and discover genetic modifiers of MFS aortopathy with the following objectives: (1) CRISPR/Cas9 correction of the recurrent FBN1 p.Ile2585Thr in patient-derived iPSC-VSMCs and functional comparison to FBN1 mutant and control iPSC-VSMCs. (2) Whole genome and RNA-sequencing of patient iPSC-VSMCs at the extreme ends of the phenotypical spectrum for genetic modifier identification. (3) CRISPR-modification for validation of their modifying capacities. The understanding of the functional effects of the FBN1 mutation and the identification of genetic modifiers will advance the knowledge on aortopathy-mechanisms beyond current understanding, it will allow to individualize treatment protocols and will offer new leads to novel therapeutic targets.

Researcher(s)

• Promoter: Loeys Bart
• Co-promoter: Meester Josephina

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

Pluripotent stem cell (PSC) technology is increasingly gaining interest for modelling diseases and developing precision therapeutics. However, the immaturity and heterogeneity of PSC-derived cell populations impinge on the reproducibility and preclude their use for comparative and diagnostic analyses. Recognizing these caveats for their own human induced (hi)PSC-based research, the Laboratories of Experimental Hematology, Cardiogenetics and Cell Biology and Histology have teamed up to develop a pipeline that enables accurate phenotypic staging of hiPSC-derived cell culture models. Specifically, to create mature and standardized 2D and 3D-models for cardiomyocyte cultures and brain organoids, our consortium proposes to optimize the culture conditions and refine the interrogation methods. Longitudinal follow-up and validation of functional activity in the differentiation products will be achieved by means of high-throughput multi-electrode array recordings and live cell calcium and voltage imaging. In parallel, cellular heterogeneity will be mapped with quantitative immunofluorescence and transcriptome analyses. The correlation of functional and molecular readouts will allow establishing a biomarker panel for mature hiPSC-derived cardiomyocyte models and brain organoids. Thus, with this work, we intend to develop more reproducible models and to allow selecting only those with the highest functional maturity, a prerequisite for our future stem cell research aimed at studying and treating neuro-inflammatory and cardiogenetic disorders.

Researcher(s)

• Promoter: Ponsaerts Peter
• Co-promoter: De Vos Winnok
• Co-promoter: Loeys Bart

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

My mission is to consolidate and expand my cardiogenetics research group of the University of Antwerp as a center of excellence that aims to identify the genetic causes and underlying pathogenetic mechanisms of both common and rare genetic disorders affecting the cardiovascular system, in particular aortic aneurysmal disorders and primary inheritable arrhythmias. It will be the ultimate goal to translate our genetic and pathomechanistic discoveries into an improvement of the quality of life of patients.

Researcher(s)

• Promoter: Loeys Bart
• Fellow: Loeys Bart

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

Cardiovascular diseases are worldwide the leading cause of mortality (31% of all deaths, WHO) and disability. These diseases include heart failure, coronary artery disease, hypertension, cerebrovascular and peripheral vascular diseases. Dysfunction of endothelial cells (ECs) lining the inner wall of the vasculature is a major initiator that fuels the progression of cardiovascular disease. Mutations in genes encoding different components of the bone morphogenetic protein (BMP) pathway cause various severe vascular diseases such as hereditary hemorrhagic telangiectasia (HHT), bicuspid aortic valve with thoracic aortic aneurysms (BAV/TAA) and pulmonary arterial hypertension (PAH) (Goumans et al., Cold Spring Harbor Persp. Biol. 2018). BMPs are secreted factors that belong to the larger transforming growth factor (TGF)β family. Signaling by BMPs contributes to the morphological, functional and molecular differences ('heterogeneity') among ECs in different vessel types like arteries, veins, lymphatic vessels and in different organs. Understanding how BMP signaling co-regulates EC heterogeneity in homeostasis and how its deregulation can contribute to disease is key to obtain insights in the genesis of vessel-type restricted disorders and design improved disease-tailored therapies with reduced side effects. The BMP pathway is an important therapeutic target in vascular disease, with several BMP modulators being used already in clinic. The BMP signaling output critically depends on the cellular context in the vessel wall which includes flow hemodynamics, inflammation, interplay with other "vascular" signaling cascades and the interaction of ECs with peri-endothelial cells and surrounding matrix. The BMP community – which has long remained bone-centered – is joining forces relatively recently in vascular biology within Europe. We feel momentum to team-up with the present multidisciplinary network consortium consisting of 8 'Flemish' teams from 3 Universities (A. Zwijsen (KUL1), E.A. Jones (KUL2), B. Loeys/A. Verstraeten (UA), A. Luttun (KUL3), R. Quarck/M. Delcroix (KUL4), P. Segers (UGent) and H. Van Oosterwyck (KUL5),) and 6 external teams (M.J. Goumans (NL1), F. Itoh (JP), P. Knaus (DE), F. Lebrin (NL2/FR2), G. Valdimarsdottir (IS) and M. Vikkula (BE)) to jointly address how i) dysfunctional BMP pathways contribute to vessel (instability) diseases, ii) how impaired BMP signaling affects mechanobiology (interpretation of flow, cellular tractions, matrix stiffness) in the vessel wall and iii) validate promising BMP-based vessel repair strategies across our different models. The various partners of this WOG network study different aspects of BMP/TGFβ signaling and/or vascular (mechano)biology and disease (see further). Within this multidisciplinary consortium, we aim to accelerate the unraveling of BMP-mediated mechanisms of EC heterogeneity and mechanotransduction to refine and improve etiology-based vascular repair strategies, a major challenge in curing vessel-related diseases. Our objectives are to: i) increase critical mass in Flanders on BMP signaling and its interplay with mechanotransduction in vascular diseases and boost trans- and interdisciplinary collaborations within this consortium, to underscore faster commonalities and specificities of (impaired) BMP functions in different vascular beds and vessel (instability) diseases; ii) model and validate vessel normalization strategies in our various physiopathological systems and translate results to a clinical setting; iii) create an "incubator" environment and solid basis for future successful funding applications (leverage); iv) expose and challenge each other's work at an early stage to strengthen and increase research output and competitiveness; v) increase visibility of all the teams in Flanders and internationally, propel the junior talents in the teams and deliver high-quality trained PhDs/masters/bachelors.

Researcher(s)

• Promoter: Loeys Bart

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

GENOMED is an interfaculty consortium of four research groups and Center of Excellence at the University of Antwerp. The general aim of GENOMED is to enhance genetic research in biomedical sciences by application of state-of-the-art technologies such as next generation sequencing (NGS), induced pluripotent stem cells (iPSC) and gene editing (CRISPR/Cas). In the past few years, GENOMED has focused on exome sequencing which has led to new gene discoveries but now anticipates that whole genome sequencing (WGS) will become the next standard genetic analysis and an essential step towards personalized medicine. The future research within GENOMED will focus on two major challenges: first, the development of technologies that allow better understanding of the biological meaning of both coding and noncoding genetic variants in the human genome, and second, the translation of these new genetic findings into better diagnostics and treatment. At present, the major bottleneck with NGS is the ability to distinguish causal mutations from benign variants. The study of the functional effect of these variants will be key in the understanding of the disease biology but also necessary for the translation into personalized medicine. It will require robust and efficient systems to explore the functional consequences of these variants by using in vitro cell cultures (especially iPSC) and/or animal models (mouse, zebrafish) that are representative for the human disorder. To address the second challenge, the consortium will establish collaborations with clinicians and industry to transfer genetic knowledge into biomarkers and to translate the new genetic insights into innovative therapies.

Researcher(s)

• Promoter: Loeys Bart
• Promoter: Mortier Geert
• Co-promoter: Kooy Frank
• Co-promoter: Loeys Bart
• Co-promoter: Van Camp Guy
• Co-promoter: Van Hul Wim

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

The maintenance contracts for our NGS devices (MiSeq and HiSeq1500) are partly covered by BOF funding. These devices were gained by Hercules funding. They make next generation sequencing for research purposes possible.

Researcher(s)

• Promoter: Loeys Bart
• Promoter: Mortier Geert

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

We apply for BOF support for involvement of Catalyze for an application in Call topic: Horizon Europe - EIC pathfinder Challenge: Cardiogenomics (HORIZON-EIC-2022-PATHFINDERCHALLENGES-01-03) Deadline October 19, 2022 Anticipated evaluation outcome: March 2023 Start project: July 2023

Researcher(s)

• Promoter: Loeys Bart

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

A progressive widening of the aorta (called aortic aneurysm) affecting our body's main blood vessel in the chest (thorax) can lead to a catastrophic event with a tear or rupture of the aortic wall (dissection or rupture). Unfortunately, a thoracic aortic aneurysm most often remains asymptomatic until catastrophic dissections or ruptures happen. These latter complications are a major cause of sudden cardiac death in the western world. Currently, aortic aneurysms are mostly detected incidentally upon imaging studies for other medical indications. Although not perfect, follow-up of the diameter of the aorta by imaging studies is considered the best predictor of the aortic dissection risk. At present, there are no markers in the blood (called biomarkers) that can predict the presence of a thoracic aortic aneurysm or the occurrence of a thoracic aortic dissection. Identification of such a biomarker would be of great help in the faster and easier diagnosis and follow-up of thoracic aortic aneurysm and dissection. Upon investigation of aneurysmal aortic gene expression profiles of three different symptomatic mouse models of Marfan and Loeys-Dietz syndrome, we observed high expression of a novel gene in all three models. This gene encodes for a growth factor that has not previously been associated with the pathogenesis of thoracic aortic aneurysm. Although the molecule has been linked to metabolism and cancer, its highest expression is in the aortic wall. In this study we would like to investigate if serum levels of this growth factor in Marfan and Loeys-Dietz syndrome mice correspond to their thoracic aortic aneurysm severity and progression. We will validate the findings in serum samples of patients with thoracic aortic aneurysm and dissection. If successful, the latter model can be used in future projects to test therapeutic compounds with the "simple" measurement of the levels of this growth factor as the outcome parameter. In summary, if successful our project will provide the strong foundations of future research that will further explore whether serum levels of this growth factor can detect asymptomatic thoracic aortic aneurysm, monitor disease progression and predict aortic dissection.

Researcher(s)

• Promoter: Loeys Bart
• Co-promoter: Verstraeten Aline

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

Financial support from University of Antwerp needed for establishing zebrafish facility for the modeling of human genetic disease. This funding will be complemented with support of the Fund for Scientific Research Flanders.

Researcher(s)

• Promoter: Loeys Bart

Research team(s)

Project type(s)

• Research Project

Abstract

Loeys-Dietz syndrome (LDS) is a genetic disorder presenting with thoracic aortic aneurysm (TAA), causing abnormal widening of the aorta, which leads to aortic rupture or dissection, a life-threatening complication that occurs unexpectedly. LDS is caused by genetic defects in six different genes of the TGF? pathway (TGFBR1/2, SMAD2/3, TGFB2/3), which is vital in the proper development of the body's connective tissue. Despite the progress in unraveling its genetic basis, there is a lack of understanding of the wide range of severity of cardiovascular involvement. In my project, I will focus on patients within families, carrying pathogenic SMAD3 variants, which show either no or early-onset aortic aneurysmal disease. I hypothesize that genetic modifiers of the primary SMAD3 mutation are the main contributors to the striking aortopathy variability in LDS-SMAD3 families. In this project, an innovative strategy will be used to identify genetic modifiers. I will perform genome-wide single nucleotide polymorphism-based linkage analysis on two large SMAD3 families and whole-genome sequencing on selected individuals, combined with SMAD3 iPSC-VSMC (induced pluripotent stem cell-derived vascular smooth muscle cells) model creation and characterization and subsequent CRISPR/Cas9-based validation of the identified modifier(s). The predicted outcomes will advance the LDS and TAA knowledge, contributing to the discovery and development of novel therapeutic targets and personalized medicine.

Researcher(s)

• Promoter: Loeys Bart
• Co-promoter: Alaerts Maaike
• Co-promoter: Verstraeten Aline
• Fellow: Velchev Joe Davis

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

Brugada syndrome (BrS) is an inherited arrhythmic disorder and is estimated to account for up to 12% of all sudden cardiac death cases, especially in the young (< 40 years old). Only in circa 30% of BrS patients the underlying genetic cause can be identified with current diagnostic arrhythmia gene panels. Moreover, the use of these panels result in detection of numerous genetic "Variants of Uncertain Significance" (so called VUS), but currently functional models to prove their causality are lacking. Therefore, in my project I will create two proof-of-concept models for a known pathogenic CACNA1C mutation associated with BrS: a cardiomyocyte cell model, created from human stem cells, and a novel transgenic zebrafish model with built-in fluorescent calcium and voltage indicators. By functionally characterising these models with innovative imaging and electrophysiological techniques, I will assess the mutation's effect on a cellular level and in the whole heart, proving its contribution to disease causation. After validating these models, I will apply this strategy to functionally assess the pathogenicity of two VUS identified in two BrS patients. Ultimately, by establishing the use of these state-of-the-art study models to predict the pathogenicity of BrS-related VUS, a more accurate risk stratification and proficient use of specialized prevention strategies can be implemented in the future, potentially also for other electrical disorders of the heart.

Researcher(s)

• Promoter: Loeys Bart
• Co-promoter: Alaerts Maaike
• Co-promoter: Knapen Dries
• Co-promoter: Labro Alain
• Co-promoter: Schepers Dorien
• Co-promoter: Snyders Dirk
• Fellow: Vandendriessche Bert

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

Sudden death in the young is primarily caused by inherited diseases of the heart. These conditions are frequently caused by mutations in genes responsible for maintaining a regular heartbeat. Many genes that can cause sudden death have already been identified. However, for an important portion of patients, the genetic test reveals a genetic variant with unknown significance. With my project, I intend to create a new model to study the effects of these mutations on the heart in vivo. For this purpose, I will generate a new zebrafish line, in which cardiac electrical and chemical calcium signals will be converted into fluorescent light signals. As zebrafish are translucent during the first days of development, this animal model lends itself perfectly to visualize these signals in vivo. I will use the new zebrafish line to improve our understanding of one specific cardiac disorder, catecholaminergic polymorphic ventricular tachycardia (CPVT). This condition is characterized by abnormal calcium signaling in the heart, and as such my method will be highly suitable to study CPVT. Both in the literature and in our own cardiogenetics clinic, several CPVT families with an uncertain inheritance pattern have been discovered. With my assay I intend to expose the mechanisms of CPVT in these families and hereby clarify the results of the genetic tests and contribute to future diagnostic testing in CPVT.

Researcher(s)

• Promoter: Loeys Bart
• Co-promoter: Alaerts Maaike
• Co-promoter: Schepers Dorien
• Fellow: Sieliwonczyk Ewa

Research team(s)

Project type(s)

• Research Project

Abstract

This project aims to upgrade the current electrophysiology technologies at UAntwerpen by acquiring a state-of-the-art MicroElectrode Array platform (MEA). To study the electrophysiological properties of excitable cells, currently patch-clamping is the gold standard. However, this is an extremely labour-intensive and invasive technique, limited to short-term measurements of individual cells at single time points. On the other hand, MEAs enable high-throughput non-invasive longitudinal real‐time measurements of functional cellular networks, without disrupting important cell-cell contacts, and thus provide a more physiologically relevant model. The multi-well format allows repeated recordings from cell cultures grown under various experimental conditions, including the opportunity to rapidly screen large drug libraries. Based on these advantages, multi-well MEAs are the most suitable instrument for functionally elucidating the pathomechanisms of neurological/cardiac disorders by performing (1) cardiac activity assays: measurement of field and action potentials from (iPSC-)cardiomyocytes to investigate wave-form, propagation and irregular beating; (2) neural activity assay based on three key measures: frequency of action potential firing, synchrony as measure for synaptic strength and oscillation as hallmark for neuronal organization in time; (3) (iPSC-)vascular smooth muscle contractility assay based on impedance alterations.

Researcher(s)

• Promoter: Loeys Bart
• Co-promoter: Kooy Frank
• Co-promoter: Labro Alain
• Co-promoter: Ponsaerts Peter
• Co-promoter: Rademakers Rosa
• Co-promoter: Snyders Dirk
• Co-promoter: Timmerman Vincent
• Co-promoter: Weckhuysen Sarah

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

The aorta is the body's main artery and supplies oxygenated blood to all parts of the body. A dilatation of the thoracic aorta leads to the development of thoracic aortic aneurysms (TAA). These weakened regions are vulnerable to tearing and this often results in sudden death. In 2016, we identified BGN (Biglycan) as a novel cause of a severe form of TAA, which is now called Meester-Loeys syndrome (MLS). In parallel with our observations, different mutations in BGN were described as the cause of X-linked spondylo-epi-metaphyseal dysplasia (X-SEMD), which is characterized by short stature. Based on the current knowledge, it remains unknown which mechanisms explain why some mutations in BGN lead to X-SEMD and others lead to MLS and why only MLS patients with BGN deletions also develop skeletal symptoms. This project aims to answer these questions by addressing the following objectives: (1) characterization of the disease phenotypes and pathomechanisms in dedicated mouse models of TAA and X-SEMD, (2) the verification of the functional differences between BGN mutations causing MLS versus X-SEMD in a human cell model and (3) the identification of the role of an alternative splice form of the biglycan protein in the development of skeletal features in MLS.

Researcher(s)

• Promoter: Loeys Bart
• Co-promoter: Meester Josephina
• Co-promoter: Mortier Geert

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

This is funding from the Flemish Government to support the genetic centers in Flanders in their key tasks such as research, teaching and patient care. The funding is renewable every year after positive evaluation of the annual activity report

Researcher(s)

• Promoter: Loeys Bart
• Promoter: Mortier Geert

Research team(s)

Project type(s)

• Research Project

Abstract

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with pleiotropic ocular, skeletal and cardiovascular manifestations. Morbidity and mortality are mostly determined by aortic root aneurysm, dissection and rupture. Although mutations in FBN1, coding for fibrillin-1, are the sole genetic MFS cause, there is a poor correlation between the MFS phenotype and the nature or location of the FBN1 variant. Wide intra- and interfamilial phenotypic variability, ranging from completely asymptomatic to sudden death at young age, is observed. The precise mechanisms underlying this variability remain elusive. In this project, I have selected an innovative strategy to fully understand the functional effects of the FBN1 mutation and discover genetic modifiers of MFS aortopathy with the following objectives: (1) CRISPR/Cas9 correction of the recurrent FBN1 p.Ile2585Thr in patient-derived iPSC-VSMCs and functional comparison to FBN1 mutation and control iPSC-VSMCs. (2) Whole genome sequencing, and RNA-seq of patient iPSCVSMCs at the extreme ends of the phenotypical spectrum for genetic modifier identification. (3) CRISPR-modification for validation of their modifying capacities. The understanding of the functional effects of the FBN1 mutation and the identification of genetic modifiers will advance the knowledge on aortopathy-mechanisms beyond current understanding, it will allow to individualize treatment protocols and will offer new leads to novel therapeutic targets.

Researcher(s)

• Promoter: Loeys Bart
• Co-promoter: Verstraeten Aline
• Fellow: Van Den Heuvel Lotte

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

Anthracyclines are the mainstay of chemotherapeutic treatment in a wide range of malignancies, including breast cancer and frequent childhood cancers. Due to a growing population of cancer-survivors, the importance of long-term complications of anti-cancer treatment has increased. Today's breast cancer patients may become tomorrow's heart failure patients. There is an important inter individual susceptibility for the development of cardiotoxicity. This variation is not fully explained by differences in clinical risk factors. Therefore, it is suggested that genetic variations may play a role. It was recently shown that genetic variants in titin, an import anchoring protein in the cardiomyocytes, can cause a predisposition to dilated cardiomyopathies that are clinically similar to chemotherapy-induced cardiotoxicity In this research project we aim to investigate whether mutations in important structural cardiac genes, more specific titin, can cause an increased susceptibility for cardiotoxicity.

Researcher(s)

• Promoter: Van Craenenbroeck Emeline
• Co-promoter: Heidbuchel Hein
• Co-promoter: Loeys Bart
• Fellow: Boen Hanne

Research team(s)

• Cardiovascular diseases (CARDIOVASC)

Project type(s)

• Research Project

Abstract

Loeys-Dietz syndrome (LDS) is a genetic disorder presenting with thoracic aortic aneurysm (TAA), causing abnormal widening of the aorta, which leads to aortic rupture or dissection, a life-threatening complication that occurs unexpectedly. LDS is caused by genetic defects in six different genes of the TGF? pathway (TGFBR1/2, SMAD2/3, TGFB2/3), which is vital in the proper development of the body's connective tissue. Despite the progress in unravelling its genetic basis, there is a lack of understanding of the wide range of severity of cardiovascular involvement. In my project, I will focus on patients within families, carrying pathogenic SMAD3 variants, which show either no or early onset aortic aneurysmal disease. I hypothesize that genetic modifiers of the primary SMAD3 mutation are the main contributors to the striking aortopathy variability in LDS-SMAD3 families. In this project, an innovative strategy will be used to identify genetic modifiers. I will perform genome-wide single nucleotide polymorphism-based linkage analysis on two large SMAD3 families and whole genome sequencing on selected individuals, combined with SMAD3 iPSC-VSMC (induced pluripotent stem cell-derived vascular smooth muscle cells) model creation and characterization and subsequent CRISPR/Cas9-based validation of the identified modifier(s). The predicted outcomes will advance the LDS and TAA knowledge, contributing to the discovery and development of novel therapeutic targets and personalized medicine.

Researcher(s)

• Promoter: Loeys Bart
• Co-promoter: Verstraeten Aline
• Fellow: Velchev Joe Davis

Research team(s)

Project type(s)

• Research Project

Abstract

Brugada syndrome (BrS) is an inherited arrhythmic disorder and is estimated to account for up to 12% of all sudden cardiac death cases, especially in the young (< 40 years old). Only in circa 30% of BrS patients the underlying genetic cause can be identified with current diagnostic arrhythmia gene panels. Moreover, the use of these panels result in detection of numerous genetic "Variants of Uncertain Significance" (so called VUS), but currently functional models to proof their causality are lacking. Therefore, in my project I will create two proof-of-concept models for a known pathogenic CACNA1C mutation associated with BrS: a cardiac muscle cell-model, created from human stem cells, and a novel transgenic zebrafish model with built-in fluorescent calcium and voltage indicators. By functionally characterising these models with innovative imaging techniques, I will assess the mutation's effect on a cellular level and in the whole heart, proving it's contribution to disease causation. After validating these models, I will apply this strategy to functionally assess the pathogenicity of two VUS identified in two BrS patients. Ultimately, by establishing the use of these state-of-the-art study models to predict the pathogenicity of BrS-related VUS, a more accurate risk stratification and proficient use of specialized prevention strategies can be implemented in the future, potentially also for other electrical disorders of the heart.

Researcher(s)

• Promoter: Loeys Bart
• Co-promoter: Alaerts Maaike
• Co-promoter: Schepers Dorien
• Fellow: Vandendriessche Bert

Research team(s)

Project type(s)

• Research Project

Abstract

The aorta is the body's main artery and supplies oxygenated blood to all parts of the body. A dilatation of the thoracic aorta leads to the development of thoracic aortic aneurysms (TAA). These weakened regions are vulnerable to tearing and this often results in sudden death. In 2016, I identified BGN (Biglycan) as a novel cause of a severe form of TAA, which is now called Meester-Loeys syndrome (MLS). In parallel with my observations, different mutations in BGN were described as the cause of X-linked spondylo-epi-metaphyseal dysplasia (X-SEMD), which is characterized by short stature. Based on the current knowledge, it remains unknown which mechanisms explain why some mutations in BGN lead to X-SEMD and others lead to MLS and why only MLS patients with BGN deletions also develop skeletal symptoms. This project aims to answer these questions by addressing the following objectives: (1) characterization of the disease phenotypes and pathomechanisms in dedicated mouse models of TAA and X-SEMD, (2) the verification of the functional differences between BGN mutations causing MLS versus X-SEMD in a human cell model and (3) the identification of the role of an alternative splice form of the biglycan protein in the development of skeletal features in MLS.

Researcher(s)

• Promoter: Loeys Bart
• Fellow: Meester Josephina

Research team(s)

Project type(s)

• Research Project

Abstract

Thoracic aortic aneurysm (TAA) entails a high risk for aortic dissection and rupture. The latter events are a prominent cause of morbidity and mortality in the Western population. Over the past 25 years, extensive gene discovery efforts have identified over 30 genes in which variants impinge on TAA risk. Although collectively explaining less than 30% of all familial patients, their identification and functional characterization have been key in acquiring the vast majority of our current knowledge on aortopathy pathomechanisms. Yet, the genetic and mechanistic picture for TAA is far from complete, hampering further identification of predictive markers for aneurysm development and progression as well as novel therapies capable of stopping or even reversing the disease process. In search for novel entry points in the etiology of TAA, I most recently identified recessive truncating mutations in IPO8 as a novel cause of a TAA syndrome clinically resembling TGF-β-related syndromes such as Marfan syndrome, Loeys-Dietz syndrome and Shprintzen-Goldberg syndrome. More precisely, patients present with childhood-onset aneurysms at the level of the aortic root and/or aorta ascendens, global developmental delay, facial dysmorphism, joint laxity, neonatal hypotonia, pectus deformity and hernia. Not much is known about IPO8, except that it encodes a protein involved in cytosol-to-nucleus cargo shuttling (including pSMAD2, pSMAD3 and SMAD4) as well as miRNA processing. My project proposal builds further on this novel genetic finding. More specifically, I aim (1) to unravel the IPO8-related pathomechanisms using patient- and control-derived skin fibroblasts and induced pluripotent stem cell-derived vascular smooth muscle cells (iPSC-VSMCs), and (2) to discover FDA-approved drug compounds for aortopathy using a matrix metalloproteinase inhibition assay in iPSC-VSMCs of an IPO8 mutation-positive patient. The project's anticipated outcomes will advance TAA knowledge significantly beyond the current understanding and improve patient management.

Researcher(s)

• Promoter: Verstraeten Aline
• Co-promoter: Loeys Bart

Research team(s)

Project type(s)

• Research Project

Abstract

Thoracic aortic aneurysm and dissection (TAAD) is an important cause of morbidity and mortality in the western world. As 20% of all affected individuals have a positive family history, the genetic contribution to the development of TAAD is significant. Over the last decade dozens of genes were identified underlying syndromic and non-syndromic forms of TAAD. Although mutations in these disease culprits do not yet explain all cases, their identification and functional characterization were essential in deciphering three key aortic aneurysm/dissection patho-mechanisms: disturbed extracellular matrix homeostasis, dysregulated TGFbeta signaling and altered aortic smooth muscle cell contractility. Owing to the recent advent of next-generation sequencing technologies, I anticipate that the identification of additional genetic TAAD causes will remain quite straightforward in the coming years. Importantly, in many syndromic and non-syndromic families, significant non-penetrance and both inter- and intra-familial clinical variation are observed. So, although the primary genetic underlying mutation is identical in all these family members, the clinical spectrum varies widely from completely asymptomatic to sudden death due to aortic dissection at young age. The precise mechanisms underlying this variability remain largely elusive. Consequently, a better understanding of the functional effects of the primary mutation is highly needed and the identification of genetic variation that modifies these effects is becoming increasingly important. In this project, I carefully selected four different innovative strategies to discover mother nature's own modifying capabilities in human and mouse aortopathy. The identification of these genetic modifiers will advance the knowledge significantly beyond the current understanding, individualize current treatment protocols to deliver true precision medicine and offer promising new leads to novel therapeutic strategies.

Researcher(s)

• Promoter: Loeys Bart

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

Thoracic aortic aneurysm (TAA) is an abnormal widening of the thoracic aorta caused by blood vessel wall weakness. TAAs entail a high risk for aortic rupture or dissection, commonly leading to sudden death. This dramatic event may leave family members of the deceased terrified and oblivious. To date, genetic defects in >30 genes have been linked with TAA, providing a molecular cause for about 30% of patients. Their identification and functional characterization have been key in acquiring our current aortopathy knowledge. Yet, the genetic and mechanistic picture for TAA is far from complete, hampering identification of predictive markers for aneurysm formation and development of therapies capable of stopping or reversing aneurysm formation. In search for novel TAA genes, the Antwerp Cardiogenetics research group most recently identified recessive truncating mutations in IPO8 as a novel cause of syndromic TAA. My PhD project builds on this exciting finding. More specifically, I aim to significantly improve our current TAA pathomechanistic insight and future TAA patient management by (1) investigating IPO8 as a novel syndromic TAA gene through characterization of an Ipo8 null mouse line, (2) elucidating the IPO8-related pathomechanisms using patient- and control-derived cell lines, and (3) identifying putative drug compounds for IPO8-related aortopathy using a cell-based matrix metalloproteinase inhibition assay.

Researcher(s)

• Promoter: Loeys Bart
• Co-promoter: Verstraeten Aline
• Fellow: Van Gucht Ilse

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

Sudden death in the young is primarily caused by inherited diseases of the heart. These conditions are frequently caused by mutations in genes responsible for maintaining a regular heartbeat. Many genes that can cause sudden death have already been identified. However, for an important portion of patients, the genetic test reveals a genetic variant with unknown significance. With my project, I intend to create a new model to study the effects of these mutations on the heart in vivo. For this purpose, I will generate a new zebrafish line, in which cardiac electrical and chemical calcium signals will be converted into fluorescent light signals. As zebrafish are translucent during the first days of development, this animal model lends itself perfectly to visualize these signals in vivo. I will use the new zebrafish line to improve our understanding of one specific cardiac disorder, catecholaminergic polymorphic ventricular tachycardia (CPVT). This condition is characterized by abnormal calcium signaling in the heart, and as such my method will be highly suitable to study CPVT. Both in the literature and in our own cardiogenetics clinic, several CPVT families with an uncertain inheritance pattern have been discovered. With my assay I intend to expose the mechanisms of CPVT in these families and hereby clarify the results of the genetic tests and contribute to future diagnostic testing in CPVT.

Researcher(s)

• Promoter: Loeys Bart
• Co-promoter: Alaerts Maaike
• Co-promoter: Schepers Dorien
• Fellow: Sieliwonczyk Ewa

Research team(s)

Project type(s)

• Research Project

Abstract

The aorta is the body's main artery and supplies oxygenated blood to all parts of the body. A dilatation of the thoracic aorta leads to the development of thoracic aortic aneurysms (TAA). These weakened regions are vulnerable to tearing and this often results in sudden death. In 2016, I identified BGN (Biglycan) as a novel cause of a severe form of TAA, which is now called Meester- Loeys syndrome (MLS). In parallel with my observations, different mutations in BGN were described as the cause of spondylo-epi-metaphyseal dysplasia (SEMD), which is characterized by short stature. Based on the current knowledge, it remains unknown which mechanisms explain why some mutations in BGN lead to X-SEMD and others lead to MLS and why only MLS patients with a BGN deletion also develop skeletal symptoms. This project aims to answer these questions by addressing the following objectives: (1) characterization of the disease phenotypes and pathomechanisms in dedicated mouse models of TAA and SEMD, (2) the verification of the functional differences between BGN mutations causing MLS versus SEMD in a human cell model and (3) the identification of the role of an alternative splice form of the biglycan protein in the development of skeletal features in MLS.

Researcher(s)

• Promoter: Loeys Bart
• Fellow: Meester Josephina

Research team(s)

Project type(s)

• Research Project

Abstract

Brugada syndrome (BrS) is an inherited electrical disorder of the heart, presenting in patients with an irregular heart rhythm. This can go unnoticed throughout life, but also lead to sudden cardiac death, typically in patients between age 25-55. At present, more than 25 genes have been identified that can explain about 30% of BrS cases. The question remains why in the same family individuals with the identical genetic alteration can live without symptoms, have few or many arrhythmia episodes or even experience sudden death. I will look for an answer to this question in a group of families with a known error in the SCN5A gene causing BrS. I will study the exact effect of this genetic error and I will compare the difference in genetic signals between a selection of patients without symptoms and patients with severe symptoms, using whole genome and RNA sequencing techniques. Since it is important to work with heart cells in this study, I will use an advanced method that allows me to create heart cells from the patient's own skin or blood cells. Analysis of the genetic signals will lead us to the 'modifier genes' responsible for the differences in BrS disease severity. Identification of these modifiers will lead to a better insight into the mechanisms causing BrS, drive the development of novel therapies and result in more accurate risk prediction and personalized management of BrS patients.

Researcher(s)

• Promoter: Loeys Bart
• Co-promoter: Alaerts Maaike
• Fellow: Simons Eline

Research team(s)

Project type(s)

• Research Project

Abstract

Expansion of a weakened region of the thoracic aorta (aneurysm; TAA) entails a high risk for aortic dissection/rupture. The latter events associate with severe internal bleedings, often resulting in sudden death. Over time, defects in more than 20 genes have been found to influence TAA predisposition. Yet, the disease's genetic and mechanistic picture is still far from complete, hampering development of amended diagnostic tools and therapies. We will further resolve the TAA puzzle by identifying novel protective and risk-inferring variants/genes and by examining their mode of action. Multiple lines of evidence suggest that some to be identified TAA genes locate to the X-chromosome. Recently, we indeed discovered TAA-causing defects in an X-linked gene, biglycan (BGN). Interestingly, in certain mouse strains protection from BGN-related TAA has been documented. We aim at mapping the protective factor and at translating its protective effect to men. A second genetic approach builds on the observation that in Turner syndrome (TS) girls lacking either the short X-arm (Xp) or the entire X-chromosome, TAA is strikingly frequent. The known X-linked TAA genes, however, locate to the long X-arm. Hence, we also aim at identifying novel Xp-located TAA genes in TS girls. Finally, to further delineate existing disease pathways or to discover novel ones, we will functionally characterize the identified protective and risk-inferring defects in patient samples and transgenic model systems.

Researcher(s)

• Promoter: Loeys Bart
• Co-promoter: Van Laer Lut
• Co-promoter: Verstraeten Aline

Research team(s)

Project type(s)

• Research Project

Abstract

Inherited cardiac arrhythmias (ICA) are a group of predominantly autosomal dominant disorders characterized by a disturbed cardiac action potential that can lead to sudden cardiac death at a young age. Although currently more than 50 genes have been associated with ICA, in roughly 70% of the patients the precise genetic cause is still unknown. Moreover, this group of diseases is genetically and phenotypically heterogeneous and in a molecular diagnostic setting many variants of unknown pathogenic significance are detected, hampering proper risk stratification and efficient patient management. In a unique interfaculty collaboration between the Centre of Medical Genetics, the Cardiology department, the Laboratory of Experimental Hematology and Laboratory for Molecular Biophysics, Physiology and Pharmacology, we envision to address these needs in a project with two major aims: the identification of novel genes implicated in ICA and the development of a new diagnostic tool that allows functional phenotypic evaluation of the effect of genetic variants detected in ICA patients and family members. The first aim will be achieved using linkage analysis and state-of-the-art whole-genome sequencing in phenotypically well-characterized but genetically unresolved families, followed by functional characterization of the identified candidate variants. The second aim will be accomplished by the construction and electrophysiological characterization of patient-specific induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs). Focusing on the Brugada syndrome (BrS) as a proof-of-principle, iPSC-CMs will be created from fibroblasts of family members carrying an identical BrS-causing mutation but with different phenotypic expression of disease severity, and of BrS patients with a variant of unknown significance in the SCN5A gen. These powerful approaches in combination with the existing expertise in the different collaborating teams, will definitely allow accomplishing the envisioned ultimate goals of the project. As a result, a genetic diagnosis in a larger proportion of ICA families will be reached and can be translated into a personalized functional interpretation of the genetic result in patients and relatives. This will introduce the concept of precision medicine, tailoring proper risk stratification and efficient use of preventive and therapeutic measures for the individual patient.

Researcher(s)

• Promoter: Loeys Bart
• Co-promoter: Heidbuchel Hein
• Co-promoter: Snyders Dirk

Research team(s)

Project type(s)

• Research Project

Abstract

Brugada syndrome (BrS) is an inherited cardiac electrical disorder, presented in patients by irregular heart rhythm. It is often asymptomatic, therefore it can be unnoticed. However it can also cause sudden cardiac death, typically in patients between age 25-55. First degree relatives have a 50% chance to develop BrS, putting a high burden on a family. Although some genes have been causally involved, for roughly 75% of the patients the genetic background is unknown. This project aims to fill this knowledge gap, by searching for novel genetic alterations implicated in BrS. We have gathered DNA samples from individuals from 10 genetically unresolved BrS families. We will sequence the whole genome of 3 selected patients per family. For the 3 largest families, we will combine sequencing with a dedicated linkage approach to identify genomic regions shared by patients. After genetic identification of new disease-causing mutations, their effects will be investigated in an advanced cell model, consisting of heart cells created from the patient's own skin cells. This allows us to mimic the environment of the heart in vitro and study what is happening at the molecular level. This will lead to better insight into mechanisms causing BrS, driving the development of novel therapies and ultimately resulting in more accurate risk prediction and personalized management of the BrS patients.

Researcher(s)

• Promoter: Loeys Bart
• Co-promoter: Alaerts Maaike
• Fellow: Nijak Aleksandra

Research team(s)

Project type(s)

• Research Project

Abstract

The aorta serves as the responsible artery for blood distribution from the heart towards the distal parts of the human body. Expansion of weakened regions of the thoracic aorta (aneuysms; TAA) entails a high risk for aortic dissection/rupture. The latter events associate with severe internal bleedings, often resulting in sudden death. As relatives of TAA patients are at high risk, genetic defects are certainly involved in disease development. Multiple lines of evidence suggest that at least one TAA-causing gene locates to a sex (i.e. the X-) chromosome: firstly, TAA is much more frequent in males and secondly, Turner syndrome (TS) girls, in whom one X-chromosome is partially or completely deleted, strikingly often present with TAA. Most recently, our research group identified genetic defects in the biglycan (BGN) gene, which is located on the long arm of the X-chromosome (Xq), causing syndromic TAA. This project partially builds on this finding. We aim at (1) elucidating the role of BGN promoter defects in non-syndromic TAA, (2) determining the downstream consequences of BGN loss and (3) identifying a genetic factor influencing manifestation of BGN-related TAA in mice. As TS patients missing the short X-arm (Xp) are more frequently affected with TAA, it is likely that an Xp-located TAA gene remains to be identified. Therefore, goal (4) encompasses identification of an Xp aortopathy gene using X-chromosome sequencing in TS patients.

Researcher(s)

• Promoter: Loeys Bart
• Fellow: Verstraeten Aline

Research team(s)

Project type(s)

• Research Project

Abstract

When cells in the body grow and take decisions such as how fast they divide or which fate they choose for their development, they need to read and interpret the genetic code. This process is facilitated by proteins that are called the cohesin complex. When these proteins are mutated, several rare diseases can ensue; these diseases are now often referred to as cohesinopathies. Several of them can cause cardiac malformations or other forms of heart disease, in addition to other features such as delayed growth, developmental delay, and others. In this project, we will study in particular two rare cohesinopathies that affect the heart, namely Cornelia de Lange (CdLS) and CAID syndrome. The goal of our study is to better understand at molecular level what these two diseases have in common, and what distinguishes them. Specifically, we are planning to pursue the following aims: 1.) We will create models of disease 'in a dish' from cells obtained in patients and controls. This will help us to find out which parts of the genetic circuitry do not function correctly in single cells. 2.) We will study animals engineered to carry the same disease-causing mutations as those found in patients. This will allow us to find out whether identical parts of the genetic circuitry are disturbed in the whole organism. 3.) We will test all known genes in cell culture to find interactors that worsen or alleviate disease in cell-based and animal models. These results will help us to better understand a group of rare, devastating disease, and permit a more rational way to identify promising drugs for clinical use

Researcher(s)

• Promoter: Loeys Bart

Research team(s)

Project type(s)

• Research Project

Abstract

Bicuspid aortic valve, a heart valve with only two leaflets instead of three, is the most common congenital heart defect with a prevalence of 1-2%. The heart defect often remains asymptomatic but at least 10% of the bicuspid aortic valve patients develop an ascending aortic aneurysm. If not detected in a timely fashion, this can lead to an aortic dissection with high mortality. In view of the prevalent nature of this heart defect, this implies an important health care problem. Historically, it was always hypothesized that abnormal blood flow across the bicuspid valve led to aneurysm formation. However in recent years, the importance of a genetic contribution has been suggested based on the high heritability and it is currently believed that the same genetic factors predispose to the developmental valve defect and the aortic aneurysm formation. The inheritance pattern is most consistent with an autosomal dominant disorder with variable penetrance and expressivity. Until now, the latter have significantly hampered the causal gene identification but the era of next generation sequencing is now offering unprecedented opportunities for a major breakthrough in this area. Through detailed signalling pathway analysis, miRNA profiling and next generation sequencing, this project will contribute significantly to resolving the genetic causes of bicuspid related aortopathy, provide critical knowledge on the pathogenesis of aortic aneurysmal disease and deliver new therapeutic targets.

Researcher(s)

• Promoter: Loeys Bart
• Fellow: Loeys Bart

Research team(s)

Project type(s)

• Research Project

Abstract

This project represents a research contract awarded by the University of Antwerp. The supervisor provides the Antwerp University research mentioned in the title of the project under the conditions stipulated by the university.

Researcher(s)

• Promoter: Mortier Geert
• Co-promoter: Kooy Frank
• Co-promoter: Loeys Bart
• Co-promoter: Van Camp Guy
• Co-promoter: Van Hul Wim

Research team(s)

Project type(s)

• Research Project

Abstract

Bicuspid aortic valve (BAV) is the most common congenital cardiac malformation with a population prevalence of 1 to 2%. Ten to twenty percent of the BAV patients develop thoracic aortic aneurysms (TAA). Untreated TAA will lead to life-threatening aortic dissections and ruptures. Therefore, it is important to identify TAA in BAV patients, to monitor continuously the progression of TAA and to treat TAA. The general aim of this project is to unravel the underlying genetic basis of BAV/TAA, to characterise the identified genes and to gain insights into the pathogenic mechanisms.

Researcher(s)

• Promoter: Loeys Bart
• Co-promoter: Van Laer Lut
• Fellow: Luyckx Ilse

Research team(s)

Project type(s)

• Research Project

Abstract

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

Researcher(s)

• Promoter: De Meyer Guido
• Co-promoter: Claeys Marc
• Co-promoter: De Keulenaer Gilles
• Co-promoter: D'Haese Patrick
• Co-promoter: Loeys Bart
• Co-promoter: Vrints Christiaan

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

In this project, we will investigate how we can apply state-of-the-art data mining methods to reveal hidden relationships between variants, with the goal of gaining new insights in the molecular pathology of heritable diseases, focusing on cognitive and cardiac disorders.

Researcher(s)

• Promoter: Kooy Frank
• Co-promoter: Laukens Kris
• Co-promoter: Loeys Bart
• Co-promoter: Van den Bulcke Tim
• Fellow: Vandeweyer Geert

Research team(s)

Project type(s)

• Research Project

Abstract

Bicuspid aortic valve (BAV), a heart valve with only two leaflets instead of three, is the most common congenital heart defect with an estimated prevalence of approximately 1-2%. The heart defect often remains asymptomatic but ascending aortic aneurysms develop in 10-20% of the bicuspid aortic valve patients. If not detected in a timely fashion, this can lead to aortic dissection with an important mortality. Due to the prevalent nature of this heart defect, bicuspid aortic valve disease presents an important health problem. Historically, it was hypothesized that abnormal blood flow across the bicuspid aortic valve led to aneurysm formation. However in recent years, an important genetic contribution has been suggested and it is currently believed that the same genetic factors predispose to the developmental valve defect and the aortic aneurysm formation. The inheritance pattern is most nsistent with an autosomal dominant disorder with variable penetrance and expressivity. Within this project, two specific aims will be pursued. Firstly, we will investigate the potential contribution of canonical and non-canonical TGFβ signaling cascades in BAV that have been firmly implicated in Marfan-related aneurysms. Secondly, we will identify the genetic basis using a state-of-the-art technique: whole exome sequencing.

Researcher(s)

• Promoter: Loeys Bart
• Co-promoter: Van Laer Lut
• Fellow: Gillis Elisabeth

Research team(s)

Project type(s)

• Research Project

Abstract

Through detailed signalling pathway analysis, miRNA profiling and next generation sequencing, this project will contribute significantly to resolving the genetic causes of bicuspid related aortopathy, provide critical knowledge on the pathogenesis of aortic aneurysmal disease and deliver a mouse model for future therapeutical trials.

Researcher(s)

• Promoter: Loeys Bart

Research team(s)

Project type(s)

• Research Project

Abstract

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

Researcher(s)

• Promoter: Loeys Bart
• Co-promoter: Van Laer Lut

Research team(s)

Project type(s)

• Research Project

Abstract

Bicuspid aortic valve is the most common congenital heart defect and is often associated with ascending aortic aneurysms. As such it presents an important health problem. The inheritance pattern is most consistent with an autosomal dominant disorder with variable penetrance and expressivity. Within this project, we will identify the genetic basis using copy number variation analysis and whole exome sequencing and we will investigate the potential contribution of TGFβ signaling cascades.

Researcher(s)

• Promoter: Mortier Geert
• Co-promoter: Loeys Bart

Research team(s)

Project type(s)

• Research Project

Abstract

The general aim of this project is to unravel the underlying genetic basis and to gain insight into the pathogenic mechanisms leading to BAV-associated aneurysm formation in order to advance the knowledge significantly beyond the current understanding. We will take advantage of the era of next generation sequencing, which is now offering unprecedented opportunities for a major breakthrough in the field of BAV/TAA.

Researcher(s)

• Promoter: Loeys Bart
• Co-promoter: Van Laer Lut
• Fellow: Gillis Elisabeth

Research team(s)

Project type(s)

• Research Project

Abstract

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

Researcher(s)

• Promoter: Loeys Bart
• Co-promoter: Van Laer Lut

Research team(s)

Project type(s)

• Research Project

Abstract

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

Researcher(s)

• Promoter: Loeys Bart
• Co-promoter: Van Laer Lut
• Fellow: Schepers Dorien

Research team(s)

Project type(s)

• Research Project

Abstract

The general aim of this project is to gain insight into the clinical course of BAV-associated TAA, into the pathogenic mechanisms leading to aneurysm formation and to unravel the underlying genetic basis. In this project we will correlate a specific subclassification of bicuspid aortic valves (Sievers classification) with cardiovascular characteristics including co-morbidity, arterial stiffness and eccentric flow patterns. In addition, we will investigate the contribution of different developmental pathways and identify the genetic basis using state-of-the-art techniques including microRNA profiling, Copy Number Variant analysis and exome sequencing.

Researcher(s)

• Promoter: Loeys Bart
• Co-promoter: Paelinck Bernard
• Co-promoter: Van Laer Lut
• Co-promoter: Vrints Christiaan

Research team(s)

Project type(s)

• Research Project

Abstract

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

Researcher(s)

• Promoter: Loeys Bart

Research team(s)

Project type(s)

• Research Project

Abstract

Aims of the project The project employs state-of-the art methodologies to explore the (patho)genetic mechanisms underlying aortic aneurysms, including their relation with ADPKD, and involves three major aims: 1. Identification of new genomic regions involved in the etiology of aortic aneurysms 2. Application of traditional positional cloning approaches using highly advanced technologies for gene discovery

Researcher(s)

• Promoter: Loeys Bart
• Co-promoter: Van Laer Lut

Research team(s)

Project type(s)

• Research Project

Abstract

With the completion of the human genome project in 2003 and its ambitious goal of sequencing the entire human genome, the field of genetic medicine has benefited from the development of resources and technology that has accelerated genetic analysis tremendously. In addition, the better understanding of the structure and the function of the human genome has lead to the development of new tools and findings that can be applied to human health and disease. This genetic revolution has opened opportunities for a personalized genomic medicine in which genetic information is used for better diagnosis, treatment and prevention of disease. In the past, the identification of disease genes was a time- and money-consuming and labor-intensive process that often took advantage of the study of large families with multiple affected individuals. By a process called positional cloning, genomic regions were identified through the analysis of the linkage of genetic markers and the disease phenotype within families. Subsequently, it often took years to identify the causal genetic variant (called mutation) in those genomic regions. Only after the identification of mutations, research of the mechanism by which mutations lead to disease could be started with the ultimate hope to find new therapeutic options. Over the last couple of years, the development of new innovative sequencing technologies, has significantly reduced the cost and increased the speed of DNA sequencing. With these next generation sequencing technologies, it has become feasible to sequence the whole genome of single individuals. In this project, we want to apply next generation sequencing technology to perform whole exome sequencing (WES). By applying the latter technique we focus the sequencing effort on the coding part of the genome (the exome) which represents approximately 1% of the human genome but is estimated to harbor about 85% of all disease causing mutations. We plan to apply this new powerful technology to accelerate the process of disease gene/mutation identification in order to enable further pathogenetic studies and to fasten the translation to clinical care. In the initial phase, we will use this strategy to study two disease groups for which the (co)promoters have a strong research record, namely aneurysmal disease and skeletal dysplasias. The strategies that we develop for these disease groups serve as a paradigm for the study of other cardiovascular diseases (such as rhythm disorders and cardiomyopathies) or more common disorders such as osteo-arthrosis and osteoporosis. Moreover, the workflow and the bio-informatics tools developed during the course of this project can be extrapolated to any human condition with a (partly) genetic basis. We will focus on three objectives. One objective aims to combine traditional linkage analysis with WES in order to identify new disease genes. Secondly, we will apply WES to facilitate the molecular screening process to identify mutations in conditions that can be caused by multiple genes. This will significantly decrease the time required for molecular confirmation of a clinical diagnosis. Thirdly, we will use WES to search the genetic cause in sporadic patients with disorders for which no obvious causal genes exist or in patients in whom all known genes were excluded. Ultimately, this project will generate the basis for further functional studies allowing a better understanding of the disease causing mechanism and will deliver a platform that can be used by other researchers to unravel the genetic basis of other diseases.

Researcher(s)

• Promoter: Mortier Geert
• Co-promoter: Loeys Bart
• Co-promoter: Van Laer Lut

Research team(s)

Project type(s)

• Research Project

Abstract

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

Researcher(s)

• Promoter: Loeys Bart
• Co-promoter: Mortier Geert

Research team(s)

Project type(s)

• Research Project

Abstract

Aortic dissection is an important cause of death in the western world with an estimated prevalence of 1-2% of total mortality. Although most dissections occur abdominal, the study of thoracic aortic aneurysms (TAA) has provided major new insights into the pathogenesis of this disease. The genetic contribution to thoracic aortic aneurysms is demonstrated to be very important as about 20% of all affected individuals have a positive family history for aneurysms. For many years, the study of a monogenic syndromic cause of thoracic aortic aneurysm, Marfan syndrome (MFS), has served as a paradigm for the study of TAA. Detailed pathogenetic studies of humans and mouse models with MFS have lead to the identification of transforming growth factor beta signaling as a key pathway in the pathogenesis of aortic aneurysms. Through the detailed clinical description and the use of state-of-the-art molecular technologies (microarray, next generation sequencing, microRNA profiling, proteomics), this project aims at the further delineation and unraveling of the pathogenesis of TAA. A better understanding of this disease will ultimately lead to better diagnostic tools, improved counseling and development of new therapeutic strategies.

Researcher(s)

• Promoter: Mortier Geert
• Fellow: Loeys Bart

Research team(s)

Project type(s)

• Research Project