Research Wim Van Hul

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

Obesity is a complex disorder (with both lifestyle and genetic factors known to play a role in its development) affecting as much as 650 million people worldwide. Moreover, it induces excessive inflammation and oxidative stress and subsequently leads to the development of comorbidities such as non-alcoholic fatty liver disease (NAFLD). With a prevalance of 25% in general population and up to 90% in the obese population, NAFLD is currenty the most common chronic liver disease worldwide. On top of that, it can progress into life-threatening diseases such as liver cirrhosis. However, treatment options remain limited, especially for more advanced disease stages, indicating a need for better disease characterisation including elucidation of genetic risk factors that predispose to its development and early diagnosis. Consequently, in this project, we will investigate the role of the anti-inflammatory and anti-oxidative proteins paraoxonase (PON) 1 and 3, which are highly expressed in liver. To this end, our preliminary results showing a correlation between PON1 and NAFLD in an obesity cohort will be validated in a pon1 knockout model in zebrafish. PON3 will be examined in an in vitro HepG2 cell model and in a human obesity cohort. Ultimately, we will unravel the role of PON1 and PON3 in obesity and obesity-associated liver disease and elucidate the possible underlying mechanisms, being inflammation and oxidative stress.

Researcher(s)

• Promoter: Van Hul Wim
• Fellow: Van Dijck Evelien

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

Obesity constitutes a major health problem, partly due to the increasing prevalence and secondly because of its associated morbidity. It is associated with increased amounts of adipose tissue as well as fat accumulation in non-adipose tissue such as liver and skeletal muscle. Accumulation of ectopic fat in the liver (non-alcoholic fatty liver disease, NAFLD) is a strong independent marker of dyslipidaemia and insulin resistance predisposing to the development of type 2 diabetes. Besides high caloric diet and lack of physical activity, pesticide exposure and endocrine disruptor pollutants are now also increasingly recognized as an "obesogenic" risk factor. Remarkably, recent genome- and epigenome wide associations studies highlight crosstalk of many obesity-associated genetic variants and environmental factors (diet, pesticides, exercise, alcohol consumption, smoking, drugs, medication) with DNA methylation changes at proximal promoters and enhancers. For example, we recently found a strong association between the paraoxonase 1 (PON1) p.Q192R genotype with pesticide exposure and adverse epigenetic (re)programming of endocrine pathways in obesity and high body fat content. PON members hydrolyze several pesticides, a number of exogenous and endogenous lactones and metabolizes toxic oxidized lipids of low density lipoproteins (LDL) and HDL. A decrease in PON1 expression promotes adverse lipid metabolism and is an important risk factor for cardiometabolic disease and has recently been found to be associated with childhood and adult obesity, liver steatosis and its more severe subtype of steatohepatitis. Differences in PON2 have been associated with obesity susceptibility in brown/white adipose tissue. Given the crucial role of PON members in protecting from adverse environmental exposure and from obesity, there is an urgent need for further molecular and clinical research on (epi)genetic PON(1-3) regulation mechanisms in this area. In this GOA, we want to further investigate associations of clinical characterized obesity phenotypes with PON(1-3) genetic variants/polymorphisms, associated epigenetic DNA methylation variation and PON(1-3) expression in samples (i.e. blood, serum, adipose or liver) of clinical patient cohorts diagnosed with obesity, NAFLD/NASH, in relation to adverse pesticide exposure or following therapeutic medical intervention (liraglutide or bariatric surgery). Functional investigation of genetic-epigenetic regulatory crosstalk of PON(1-3) expression in response to pollutant exposure or following medical interventions will be further investigated in relation to biochemical parameters of obesity/liver steatosis/adipocyte differentiation in cell models in vitro as well as in zebrafish in vivo. As such, a better understanding of variable PON(1-3) regulation of obesity-associated traits by adverse obesogenic pollutants or healthy intervention strategies may offer new perspectives to prevent obesity and/or promote cardiometabolic health.

Researcher(s)

• Promoter: Van Hul Wim
• Co-promoter: Francque Sven
• Co-promoter: Knapen Dries
• Co-promoter: Vanden Berghe Wim

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

Bone metabolism is a complex process which is not only important during the development of the skeleton with the regulation of bone growth but also throughout life to maintain bone mass and bone strength. In our research group, we investigate the genetic cause of several skeletal dysplasias marked by abnormal bone mass or growth. In the past, this already resulted in the identification of several disease causing genes. With this project, we aim to further elucidate the role of two of these disease causing genes, namely LRP4 and NPR3, in the regulation of respectively bone mass and bone growth. Lrp4 is a modulator of the canonical WNT signaling pathway which is well known for its role in the regulation of bone formation. Previous to this project, we generated and phenotypically characterized a mouse model with a mutation in Lrp4. As this mouse has a highly increased bone mass, we aim to further elucidate the mechanism whereby LRP4 regulates bone formation by performing additional in vitro and in vivo studies. In addition, more recently, we demonstrated that loss of function mutations in NPR3 result in skeletal overgrowth among other features. Since in literature, three different functions are described for the NPR3 receptor, we aim to further investigate the role of NPR3 in the regulation of the natriuretic signaling pathway and bone growth by performing several in vitro experiments. We believe that this study will increase the insights into regulation of bone metabolism.

Researcher(s)

• Promoter: Van Hul Wim
• Co-promoter: Mortier Geert
• Fellow: Boudin Eveline

Research team(s)

Project type(s)

• Research Project

Abstract

The requested funding will be used to actively sustain the fruitful ongoing collaborations between the five research groups mentioned below. Each of the five groups have their own complementary expertise in the field of bone development, bone metabolism and modeling and molecular analysis of heritable bone disorders. The general research focus of the different groups is to identify the causal gene mutations and to elucidate the pathophysiological mechanisms involved in monogenic bone disorders, including fragile bone disorders such as Osteogenesis Imperfecta (OI) and sclerosing bone disorders such as osteopetrosis. This approach is of importance to also reveal the contribution of specific pathogenic mechanisms underlying complex bone disorders such as osteoporosis. The final goal is to open new therapeutic avenues for the treatment of heritable fragile bone disorders.

Researcher(s)

• Promoter: Van Hul Wim

Research team(s)

Project type(s)

• Research Project

Abstract

Bone may look static, but it is a highly dynamic organ in which the tissue is continuously broken down and formed anew by osteoclasts and osteoblasts, respectively. A disturbance between the activities of these cells leads to bone diseases. Paget's disease of bone (PDB) is the second most prevalent bone disorder, affecting 2-5% of Caucasian individuals >55 years of age. PDB is caused by defects in the bone-resorbing osteoclasts which become hyperactive, leading to focal skeletal lesions. For a minority of cases, a clear genetic cause has been identified. Mutations in the sequestosome 1 (SQSTM1) gene can be found in 20% of patients and account for 50% of familial cases. Recent genetic studies led to the association of 7 loci with PDB. Several genes found at these loci are involved in NF-kB signaling. We looked for variation in the genes that encode different components of the pathway in PDB patients, and identified interesting variants in the CBL, CBLB and NR4A1 genes. These genes act as a break on osteoclast formation and activity. During this project, we will study the effect of variants on signaling intensity and the formation and activity of osteoclasts. Ultimately, we will study the variant's effect on the skeletal system in zebrafishes. This will demonstrate the role that genes play in the disease mechanism in vivo, hereby giving us a deeper understanding of the human disease process and could offer opportunities for the development of new therapeutics.

Researcher(s)

• Promoter: Van Hul Wim
• Co-promoter: Mortier Geert
• Fellow: De Ridder Raphaël

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

Genetic studies demonstrated that variation in LRP4 has an important role in the regulation of bone mass both in monogenic and complex disorders. As a consequence, the main objective of this study is to further elucidate the mechanism whereby LRP4 regulates the Wnt signaling pathway.

Researcher(s)

• Promoter: Van Hul Wim

Research team(s)

Project type(s)

• Research Project

Abstract

The aim of SYBIL is to carry out extensive functional validation of the genetic determinants of rare and common skeletal diseases and the age related factors contributing to these painful conditions. To achieve this goal SYBIL will gather complementary translational and transnational scientists, systems biologists, disease modellers, leading SMEs and industrialists that will perform in-depth characterisation (complete molecular phenotyping) of pre-clinical models (cellular and animal) for a variety of common and rare skeletal diseases.

Researcher(s)

• Promoter: Van Hul Wim

Research team(s)

Project type(s)

• Research Project

Abstract

Therefore, the aim of this study is to further elucidate the role of LRP4 in the Wnt/β-catenin dependent signalling pathway and in the regulation of bone formation. In order to achieve our goal several functional experiments will be performed in vitro and we will evaluate the effect of sclerosteosis causing LRP4 mutations in vivo in mice. This increased knowledge of the role of LRP4 in the regulation of Wnt/β-catenin signalling and bone formation will result in novel opportunities for the development of therapeutics for osteoporosis.

Researcher(s)

• Promoter: Van Hul Wim
• Fellow: Boudin Eveline

Research team(s)

Project type(s)

• Research Project

Abstract

Obesity is a chronic condition characterized by an excess amount of adipose tissue which causes several health consequences. Numerous studies have shown that obesity is strongly influenced by genetic factors, with heritability estimates in the range of 80%. Although most of the results of GWASs have been highly reproducible, they explain merely 1.5% of the BMI variation in human populations. With this project we'll gain insight into the role of five candidate genes and we'll better understand the importance of copy number variation in the pathogenesis of obesity.

Researcher(s)

• Promoter: Van Hul Wim
• Co-promoter: Van Gaal Luc
• Fellow: Aerts Evi

Research team(s)

Project type(s)

• Research Project

Abstract

The aim of this project is to develop a next generation sequencing (NGS) platform to advance in a collaborative way biological and medical research within the Antwerp research community. The consortium involves more than 16 research groups in various disciplines of medicine, biology and biomedical informatics. The goals are to identify new genes and mutations in various rare Mendelian disorders, to achieve more insights in the genetic causes of cancer and to unravel more precisely the genetic determinants of infectious diseases. This new knowledge will improve both the diagnosis and management of these human diseases. The project will also focus on the interaction between environment and genes. More specifically, the effect of environmental stressors on genetic variation in aquatic organisms, the effect of teratogenic factors on embryonic development in vertebrates and the effects of environmental conditions on growth in maize and Arabidopsis lines will be studied. The analysis of the large amount of genomic and transcriptomic data, generated by the various research groups, will be coordinated by the recently founded UZA/UA bioinformatics group Biomina

Researcher(s)

• Promoter: Mortier Geert
• Co-promoter: Beemster Gerrit
• Co-promoter: Blust Ronny
• Co-promoter: Goossens Herman
• Co-promoter: Knapen Dries
• Co-promoter: Laukens Kris
• Co-promoter: Peeters Marc
• Co-promoter: Van Hul Wim
• Co-promoter: Vrints Christiaan

Research team(s)

Project type(s)

• Research Project

Abstract

The aim of the BeMGI project is to establish a vibrant network devoted to medical genomics, including Belgian top scientists active in the field of human genetics, in order to: (i) boost individual research efforts towards understanding the biology of disease by promoting collaborative exploitation of the most advanced genomic tools. (ii) develop approaches to predict clinical outcome from genomic information and fulfil a pilot role towards concerted integration of genomic information in clinical care in Belgium. (iii) play a catalyzing role in preparing the next generation of genomics researchers, informing medical practitioners about evolving trends in medical genomics, and conducting public outreach.

Researcher(s)

• Promoter: Van Camp Guy
• Co-promoter: Van Hul Wim

Research team(s)

Project type(s)

• Research Project

Abstract

In this project, we aim to identify and characterize the gene underlying an autosomal dominant disease named Hyperostosis Cranialis Interna as the patients present with an increased thickness of the skull while the remaining of the skeleton seems to be unaffected. With this project we hope to gain insight into the pathogenesis of HCI and based on that also the aspects of bone formation, especially those that might be specific to the skull bones.

Researcher(s)

• Promoter: Van Hul Wim

Research team(s)

Project type(s)

• Research Project

Abstract

This research aims to study the effect of other 'sclerostin-binding partners -on their own or through interaction with other modulator proteins- on Wnt/β-catenin signaling and on in vitro bone formation. In patients with a highly increased BMD, we will perform genetic analysis of the selected candidate genes in order to reveal new mutations. Obviously, these will be evaluated for their effect on the protein's function.

Researcher(s)

• Promoter: Van Hul Wim
• Fellow: Fijalkowski Igor

Research team(s)

Project type(s)

• Research Project

Abstract

This research aims to study the effect of other 'sclerostin-binding partners -on their own or through interaction with other modulator proteins- on Wnt/β-catenin signaling and on in vitro bone formation. In patients with a highly increased BMD, we will perform genetic analysis of the selected candidate genes in order to reveal new mutations. Obviously, these will be evaluated for their effect on the protein's function.

Researcher(s)

• Promoter: Van Hul Wim
• Fellow: Fijalkowski Igor

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: Van Hul Wim
• Fellow: Borra Vere

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: Van Hul Wim
• Fellow: Boudin Eveline

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: Van Hul Wim

Research team(s)

Project type(s)

• Research Project

Abstract

The general aim of the project is to gain novel insights into bone metabolism, especially in the resorption process by studying genes that underlie osteopetrosis. These results will contribute to improve the molecular diagnostics and genetic counseling of families affected with this disease. Besides this, new insights could finally lead to new therapeutical applications and a better prevention of osteoporosis.

Researcher(s)

• Promoter: Van Hul Wim

Research team(s)

Project type(s)

• Research Project

Abstract

This project aims to contribute ot the understanding of the pathogenesis of obesity. On the one hand we will focus on the melanocortine signaling pathyway and on the other hand other candidate genes will be studied. This will be performed by mutation and genetic association studies.

Researcher(s)

• Promoter: Van Hul Wim
• Fellow: Zegers Doreen

Research team(s)

Project type(s)

• Research Project

Abstract

This project is based on the results regarding resistin obtained during a previous project. Its main objective is to investigate the role of resistin in the development of obesity and osteoporosis. To achieve this, we will study the influence of resistin on different cellular levels, from the mesenchymal stem cell to the mature osteoblast and adipocyte, and also on a genetic level.

Researcher(s)

• Promoter: Van Hul Wim
• Fellow: Beckers Sigri

Research team(s)

Project type(s)

• Research Project

Abstract

It is recently hypothesised that the disturbance of weight homeostasis leading to obesity in humans might at least partially be influenced by endocrine disrupting chemicals. This study particularly investigates the accumulation and role of older and new emerging endocrine disrupting chemicals in the pandemic of the 21st century called obesity. The effects are studied at molecular, cellular and organism level using in vitro and in vivo approaches, analytical techniques, cell culture, genomics, genetics and epidemiological data in humans.

Researcher(s)

• Promoter: Jorens Philippe
• Co-promoter: Blust Ronny
• Co-promoter: Neels Hugo
• Co-promoter: Van Gaal Luc
• Co-promoter: Van Hul Wim

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Van Hul Wim
• Fellow: Boudin Eveline

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Van Hul Wim
• Fellow: Borra Vere

Research team(s)

Project type(s)

• Research Project

Abstract

This study will focus on the Plekhm1 gene which we recently identified to be causative for a form of osteopetrosis. Furthermore, by studying another osteopetrotic ratmodel, we hope to identify a currently unknown gene involved in bone resorption.

Researcher(s)

• Promoter: Van Hul Wim

Research team(s)

Project type(s)

• Research Project

Abstract

This EU-funded research project aims the study of wnt-signalling in bone formation and bone remodelling. This will makes it possible to evaluate its potential as a therapeutic target for the treatment of osteoporosis

Researcher(s)

• Promoter: Van Hul Wim

Research team(s)

Project type(s)

• Research Project

Abstract

This project aims to contribute ot the understanding of the pathogenesis of obesity. On the one hand we will focus on the melanocortine signaling pathyway and on the other hand other candidate genes will be studied. This will be performed by mutation and genetic association studies.

Researcher(s)

• Promoter: Van Hul Wim
• Fellow: Zegers Doreen

Research team(s)

Project type(s)

• Research Project

Abstract

Secreted Frizzled-related proteins (sFRP's) are extracellular antagonists able to modulate canonical Wnt signalling. Preliminary studies suggest a function in the process of osteoblastic bone formation for this family of proteins. In vitro and in vivo functional studies will enable us to evaluate the function of these proteins in the bone formation process.

Researcher(s)

• Promoter: Balemans Wendy
• Promoter: Van Hul Wim

Research team(s)

Project type(s)

• Research Project

Abstract

With this project we aim to contribute to the search for genetic factors involved in the pathogenesis of obesity, a disease characterized by excess fat storage. This disease is accompanied by several co-morbidities of which insulin resistance is most prevalent. Our research objectives are the following: first, we will evaluate the role of monogenic obesity in the Belgian population by performing mutation analysis of 6 functional candidate genes and by performing a linkage study to discover a new gene. Our second objective is to evaluate the role of complex obesity which we will study by means of association studies with our selected candidate genes. Achieving these goals will contribute substantially to the knowledge about the etiology of obesity and its associated insulin resistance. This knowledge will lead to the development of new and better treatment of the disease.

Researcher(s)

• Promoter: Van Hul Wim
• Fellow: Beckers Sigri

Research team(s)

Project type(s)

• Research Project

Abstract

European network to promote research into uncommon cancers in adults and children: Pathology, Biology and Genetics of Bone Tumors. (EuroBoNet) Primary bone tumours are rare, accounting ~0.2% of the cancer burden. Children and young adolescents are frequently affected. Their aggressiveness has major impact on morbidity and mortality. Though progress has been made in pathological and genetic typing, the aetiology is largely unknown. Though advances in therapeutic approaches increased survival, significant numbers of patients (~40%) still die. Within the EuroBoNeT integration will be achieved by staff exchange and website-based discussion forums to increase and disseminate knowledge of primary bone tumours at the molecular level for development of new tools for patient care and cure and technology. With this integration exchange of material (virtual BioBank), Standard Operating Protocols and the use of technology platforms will enable us to obtain statistical significant datasets, otherwise not achievable due to the rareness and large number of sub entities. A joint programme will contribute in obtaining molecular portraits of tumours, separated in 4 research lines (RL). In each RL the biology of the separate group (RL1: cartilaginous tumours; RL2: osteogenic tumours and related sarcomas; RL3: osteoclastogenesis and Giant cell tumours of bone; and RL4: Ewing family of tumours) will be examined by genome wide expression and genomic aberration studies. More specific hypothesis driven approaches will be investigated by RNA/protein expression and mutation analysis. Knowledge on normal growth and differentiation will be gathered through in vitro studies. This would lead to further understanding and identification of markers for malignant transformation and/or progression, as well as identification of therapeutic targets. Next to research, dissemination of knowledge will be achieved by training courses on bone and soft tissue pathology for all interested. The last is required since patients usually do not present themselves at centres, which necessitates spreading of knowledge.

Researcher(s)

• Promoter: Wuyts Wim
• Co-promoter: Van Hul Wim

Research team(s)

Project type(s)

• Research Project

Abstract

This project is a logical continuation of our research during the previous years resulting in the identification of several genes involved in bone metabolism and balance. Further functional characterization of these genes will provide better insight into the pathogenesis as well as the putative therapeutic applications for the prevention and treatment of osteoporosis.

Researcher(s)

• Promoter: Van Hul Wim

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Van Hul Wim
• Fellow: Perdu Bram

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Van Hul Wim
• Fellow: Piters Elke

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Van Hul Wim
• Fellow: Van Wesenbeeck Liesbeth

Research team(s)

Project type(s)

• Research Project

Abstract

The general aim of the proposed study is to contribute to the elucidation of important bone formation processes. For this, we will focus on two metabolic pathways involved in osteoblastic bone formation, more specifically those in which sclerostin and LRP5 participate. On the one side we aim to identify regulatory elements necessary for the expression of SOST in bone. On the other side we want to gain insight into the role of sclerostin and LRP5 and their pathways in bone tissue with the main emphasis on the putative interaction between both metabolic ways.

Researcher(s)

• Promoter: Van Hul Wim
• Fellow: Balemans Wendy

Research team(s)

Project type(s)

• Research Project

Abstract

This project aims the characterization of a gene we recently identified causing disturbed bone resorption in the osteopetrotic "incisors absent" rat. Functional characterization as well as the evaluation of its role in human bone homeostasis is aimed. The data generated might become a basis for further studies towards therapeutic applications for the prevention or treatment of osteoporosis.

Researcher(s)

• Promoter: Van Hul Wim

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Van Hul Wim
• Co-promoter: Van Camp Guy

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

To reach our goals, this research projects consists of three parts. First, we will try to gain insight into the level of inflammation in patients both by biochemical tests and by the study of fat tissue. Next, genetic studies will be performed to identify susceptibility genes for obesity. Obviously in this project, we will focus on genes that might influence inflammation. Finally, we will try to find association between both biochemical, histological and genetic data and clinical endpoints.

Researcher(s)

• Promoter: Van Gaal Luc
• Co-promoter: Van Hul Wim

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

With this project we aim to contribute to the search for genetic factors involved in the pathogenesis of obesity, a disease characterized by excess fat storage. This disease is accompanied by several co-morbidities of which insulin resistance is most prevalent. Our research objectives are the following: first, we will evaluate the role of monogenic obesity in the Belgian population by performing mutation analysis of 6 functional candidate genes and by performing a linkage study to discover a new gene. Our second objective is to evaluate the role of complex obesity which we will study by means of association studies with our selected candidate genes. Achieving these goals will contribute substantially to the knowledge about the etiology of obesity and its associated insulin resistance. This knowledge will lead to the development of new and better treatment of the disease.

Researcher(s)

• Promoter: Van Hul Wim
• Fellow: Beckers Sigri

Research team(s)

Project type(s)

• Research Project

Abstract

This research project aims at the characterization of natural variants in candidate genes for Paget's disease of bone in a large cohort of patients. This might contribute to the understanding of the pathogenesis of this condition characterized by an increased bone turnover.

Researcher(s)

• Promoter: Van Hul Wim

Research team(s)

Project type(s)

• Research Project

Abstract

This research project aims at identifying new genes involved in osteoblast differentiation, but also builds on the functional TGF-b1 studies performed during my PhD. The first goal will be achieved by performing a functional screen with a siRNA library: selective knock-down of genes that are possibly involved in the differentiation of osteoblast precursors, can identify those genes that influence this process. Our second goal will be to answer some of the remaining questions regarding signaling by TGF-b1 mutant proteins. Points to investigate are: Demonstration of the presence of an intracrine signaling pathway, for which we find indication in the signaling mode of type 2 mutants; Construction of a knock-in mouse model for in vivo and in vitro studies of the functioning of mutant TGF-b1 in bone metabolism; Look into the role of the latent TGF-b binding protein (LTBP) in the phenotypic manifestation of the mutations.

Researcher(s)

• Promoter: Van Hul Wim
• Fellow: Janssens Katrien

Research team(s)

Project type(s)

• Research Project

Abstract

Sclerosing bone dysplasias are characterized by an increased bone density. In the last few years, the molecular genetics of the above mentioned bone diseases has largely been elucidated by the identification of two genes, SOST and LRP5. Mutations in these genes cause bone conditions which are characterized by similar radiological symptoms, being endosteal cortical thickening of the long bones and the skull. This project will focus on the elucidation of the functional role of SOST and LRP5 in bone tissue. A first objective is to study the regulation of SOST gene transcription. Whereas the expression of this gene is largely restricted to areas in bone with active osteogenesis, being osteocytes and osteoblasts, its regulation will mainly be studied in cell lines with an osteoblast and osteocyte phenotype. We will characterize the minimal SOST promoter and additionally we will try to identify enhancer and silencer elements. The second objective is to study a potential interaction between the metabolic pathways in which the SOST gene product sclerostin and the LRP5 protein are involved using in vitro cell systems. Initial experiments will focus on the effect of sclerostin on the LRP5/Wnt signal transduction pathway. If modulation is observed, we will search for bindingspartner(s) of sclerostin. The knowledge of the regulation of SOST expression and of the suggested interaction between sclerostin and the Wnt/LRP5 signal transduction pathway will contribute to elucidate part of the complex processes in bone metabolism and homeostasis, and in particular of the mechanisms by which osteoblastic bone formation is inhibited.

Researcher(s)

• Promoter: Van Hul Wim
• Fellow: Balemans Wendy

Research team(s)

Project type(s)

• Research Project

Abstract

Osteoporotic fractures are a major healthcare problem in Europe and this is set to increase as the proportion of the elderly individuals in the population expands. This proposal will advance understanding of the mechanisms responsible for bone formation, with the long-term aim of harnessing this knowledge to develop new anabolic agents for osteoporosis. These aims will be achieved by drawing leading European academic research groups together with SME's working in bone metabolism to define the mechanisms of bone formation and uncover pathways that can be targeted for therapeutic intervention.

Researcher(s)

• Promoter: Van Hul Wim

Research team(s)

Project type(s)

• Research Project

Abstract

Osteoporosis is a common age-related disease with a strong genetic component. Gene polymorphisms which predispose to osteoporosis are the most promising risk factors. The aim of the project is to quantify the effect of osteoporosis risk genes, to study the influence of calcium-intake on these effects and to study the effect of genotype on response to treatment with hormone replacement therapy. Meta-analysis of Europe's largest population studies on osteoporosis is used to detect small, but clinically important risks. The project will result in a collection of osteoporosis risk-alleles with quantified risks, which will improve clinical risk-assessment for osteoporosis.

Researcher(s)

• Promoter: Van Hul Wim

Research team(s)

Project type(s)

• Research Project

Abstract

The aim of this project is to gain better insights in the processes that balance bone formation and bone resorption. This will be obtained by the identification and characterization of genes responsible for osteopetrosis, a condition characterized by deficient bone resorption resulting in increased bone density. Both human forms of osteopetrosis and the tl/tl and ia/ia osteopetrotic models will be studied.

Researcher(s)

• Promoter: Van Hul Wim
• Fellow: Van Wesenbeeck Liesbeth

Research team(s)

Project type(s)

• Research Project

Abstract

Visceral abdominal obesity is a major risk factor for cardiovascular disease and for the development of type 2 diabetes. Since abdominal fat accumulation is partly genetically determined, we will perform mutation analyses, association and linkage studies of polymorphisms in candidate genes for obesity, in order to identify genes which are possibly involved in the development of abdominal obesity and associated comorbidity.

Researcher(s)

• Promoter: Van Gaal Luc
• Co-promoter: Van Hul Wim

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

This project clusters four research teams of the Center of Medical Genetics at the University of Antwerp in the field of bone disorders, hereditary deafness, mental retardation and psychiatric genetics. The general aims, shared over the different research topics are localisation of disease causing genes, identification of disease causing genes, functional analysis of newly identified genes, and exploring therapeutic possibilities in animal models, based on the results of the functional analysis.

Researcher(s)

• Promoter: Nöthen Markus
• Promoter: Van Camp Guy
• Co-promoter: Kooy Frank
• Co-promoter: Van Camp Guy
• Co-promoter: Van Hul Wim

Research team(s)

Project type(s)

• Research Project

Abstract

This project aims the functional analysis of the EXTL1 gene. By mutation analysis of this gene in different types of tumours its putative tumour suppressor capacity will be checked. Besides this we will try to elucidate the function of this gene and its protein by expression studies, the construction of a knockout mouse etc.

Researcher(s)

• Promoter: Van Hul Wim
• Co-promoter: Wuyts Wim
• Fellow: Mathysen Danny

Research team(s)

Project type(s)

• Research Project

Abstract

Recently our team isolated the Alx4-gene and demonstrated that loss of function mutations in this gene can cause Foramina Parietalia Permagna. This disorder is characterized by large round to oval skull ossification defects at birth which can persist for a long time. Very little is known about the function of the ALX4-gene and its exact regulation. In this project we will examine these aspects. In one part of the project, we will investigate whether mutations in Alx4 can cause other skull defects as well such as Adams-Oliver syndrome and craniosynostosis. Next, we will try to elucidate the exact function of Alx4 and how it is regulated. This will be done with luciferase reporter assays, yeast one hybrid and yeast two hybrid techniques.

Researcher(s)

• Promoter: Van Hul Wim
• Fellow: Verdyck Pieter

Research team(s)

Project type(s)

• Research Project

Abstract

Camurati-Engelmann disease is a rare disease with an autosomal dominant inheritance. It is characterized by progressive hyperostosis of the long tubular bones. Severe cases also show hyperostosis of skull and vertebrae. The main clinical features are muscle weakness, a waddling gait and severe pain in the legs. Until now, the localisation of the responsible gene and the underlying pathogenetic mechanism are unknown. It is our aim to clarify this by positional cloning. In a first phase, we started a genomewide search on an large Israeli family.

Researcher(s)

• Promoter: Van Hul Wim
• Fellow: Janssens Katrien

Research team(s)

Project type(s)

• Research Project

Abstract

Osteoporosis is a condition of high prevalence characterized by a decreased bone density resulting in an increased risk for bone fractures. A high proportion of both male and female osteoporosis cases are caused by the administration of glucocorticoids. These are often used as a treatment for allergic and rheumatological problems because of their anti-inflammatory nature. The aim of this project is to identify the genetic factors that underly the phenotypical variability after glucocorticoid therapy. Therefore, polymorphisms in candidate genes will be checked for an association with glucocorticoid-induced osteoporosis.

Researcher(s)

• Promoter: Van Hul Wim
• Fellow: Van Driessche Karen

Research team(s)

Project type(s)

• Research Project

Abstract

The general aim of this study is the molecular and functional analysis of genes involved in bone formation and remodeling identified by positional cloning in hereditary bone disorders. The specific objectives of this project are twofold. The first part aims the identification of genes responsible for Paget's disease of bone (PDB), a frequent bone disorder affecting up to 5% of the population above 55 in the western world. The second part involves the functional analysis of genes involved in skull development. Paget's disease of bone (PDB) is characterized by increased bone resorption with a subsequent increased formation of poorly organized bone.To identify additional genes which can cause PDB, we are currently performing a genome wide screen in a large Spanish and American PDB family. Once a localization for the PDB causing gene in these families will be obtained, additional polymorphic markers will be analyzed to reduce the candidate region and genes and new transcripts from the candidate regions will be screened to identify the PBD causing mutation. Functional analysis of the PDB causing genes will then reveal the exact mechanism underlying this disease In a second part we will concentrate on the study of the ALX/MSX homeoboxgenes which where previously shown to be involved in skull development. To further characterize the exact function and regulation of the ALX4 gene we will isolate and identify flanking regulatory sequences by making deletion constructs of the ALX4 promotor region and analyzing the regulatory effects of these deletions by luciferase reporter gene assay. In addition the mouse Alx4 promotor will be characterized to identify potential conserved regulatory sequences. Additionally, further isolation, detailed physical mapping and functional characterization of potential new members of these gene families may elucidate their exact function and may reveal whether mutations in these genes also lead to defects in skull development.

Researcher(s)

• Promoter: Van Hul Wim
• Fellow: Wuyts Wim

Research team(s)

Project type(s)

• Research Project

Abstract

In this project a genetic associationstudy will be performed for some candidate genes for osteoporosis. Bone Mineral Density (BMD) is a trait influenced by several genes in combination with environmental factors. To evaluate the role of some candidate genes, they will be screened for polymorphisms which will consequent I y be analysed in an extended, weIl characterized set of individuals from Northeast Scotland to evaluate for a possible association with BMD.

Researcher(s)

• Promoter: Van Hul Wim

Research team(s)

Project type(s)

• Research Project

Abstract

The aim of this project is to gain better insights in the processes that balance bone formation and bone resorption. This will be obtained by the identification and characterization of genes responsible for osteopetrosis, a condition characterized by deficient bone resorption resulting in increased bone density. Both human forms of osteopetrosis and the tl/tl and ia/ia osteopetrotic models will be studied.

Researcher(s)

• Promoter: Van Hul Wim
• Fellow: Van Wesenbeeck Liesbeth

Research team(s)

Project type(s)

• Research Project

Abstract

This project aims the localization and identification of genes relevant for rheumatic conditions by analysis of monogenic diseases with a clnical picture close to these frequent multifactorial conditions.

Researcher(s)

• Promoter: Van Hul Wim

Research team(s)

Project type(s)

• Research Project

Abstract

Van Buchem's disease is a rare, recessive disorder characterized by an increased bone density. Recently, we were able to localize the gene. This project aims at the identification and the study of the gene involved.

Researcher(s)

• Promoter: Van Hul Wim
• Fellow: Balemans Wendy

Research team(s)

Project type(s)

• Research Project

Abstract

This project aims the functional analysis of the EXTL1 gene. By mutation analysis of this gene in different types of tumours its putative tumour suppressor capacity will be checked. Besides this we will try to elucidate the function of this gene and its protein by expression studies, the construction of a knockout mouse etc.

Researcher(s)

• Promoter: Van Hul Wim
• Fellow: Mathysen Danny

Research team(s)

Project type(s)

• Research Project

Abstract

Camurati-Engelmann disease is a rare disease with an autosomal dominant inheritance. It is characterized by progressive hyperostosis of the long tubular bones. Severe cases also show hyperostosis of skull and vertebrae. The main clinical features are muscle weakness, a waddling gait and severe pain in the legs. Until now, the localisation of the responsible gene and the underlying pathogenetic mechanism are unknown. It is our aim to clarify this by positional cloning. In a first phase, we started a genomewide search on an large Israeli family.

Researcher(s)

• Promoter: Van Hul Wim
• Fellow: Janssens Katrien

Research team(s)

Project type(s)

• Research Project

Abstract

This project aims at the cloning of FRA12A, a fragile site on chromosome 12913.1, found in a number of patients with mental retardation and/or psychiatrie abnormalities and at the identification of the gene associated with FRAl 2A.

Researcher(s)

• Promoter: Van Hul Wim
• Fellow: Schoepen Isabelle

Research team(s)

Project type(s)

• Research Project

Abstract

Camurati-Engelmann disease is a rare disease with an autosomal dominant inheritance. It is characterized by progressive hyperostosis of the long tubular bones. Severe cases also show hyperostosis of skull and vertebrae. The main clinical features are muscle weakness, a waddling gait and severe pain in the legs. Until now, the localisation of the responsible gene and the underlying pathogenetic mechanism are unknown. It is our aim to clarify this by positional cloning. In a first phase, we started a genomewide search on an large Israeli family.

Researcher(s)

• Promoter: Van Hul Wim
• Fellow: Janssens Katrien

Research team(s)

Project type(s)

• Research Project

Abstract

This project aims at the localisation and identification of genes predisposing to Paget's disease by performing genetic linkage studies in families.

Researcher(s)

• Promoter: Van Hul Wim

Research team(s)

Project type(s)

• Research Project

Abstract

This project aims at the identification of genes for human hereditary disorders by positional cloning. The physiological function and the underlying pathogenic mechanisms will be studied. The project will focus on the fragile X-syndrome, deafness and bone dysplasias.

Researcher(s)

• Promoter: Van de Heyning Paul
• Co-promoter: Van Camp Guy
• Co-promoter: Van Hul Wim

Research team(s)

Project type(s)

• Research Project

Abstract

Van Buchem's disease is a rare, recessive disorder characterized by an increased bone density. Recently, we were able to localize the gene. This project aims at the identification and the study of the gene involved.

Researcher(s)

• Promoter: Van Hul Wim
• Fellow: Balemans Wendy

Research team(s)

Project type(s)

• Research Project