Ongoing projects

Deciphering the role of Piezo1 in age-specific loss of mechanosensation in the skeleton in vivo. 01/04/2021 - 31/03/2022

Abstract

Our skeleton is a highly dynamic organ reacting to the presence or absence of mechanical stimuli in a way that regular exercise has anabolic and advantageous effects on skeletal strength, whereas physical inactivity easily results in bone loss. Physical activity is therefore also a cornerstone in the prevention and treatment of several common disorders typifying our society nowadays, like osteoporosis. Characterized by severe bone loss and skeletal fractures, osteoporosis mostly affects people above the age of 50, i.e. the physically less active. However, young adults also have more sedentary lifestyles nowadays, with (temporary or otherwise) detrimental effects on their skeletal strength. Although these effects of mechanical stimuli on the skeleton are widely recognized, the mechanisms driving the translation of mechanical stimuli into the appropriate cellular and molecular response remain largely elusive. Very recently, the Piezo1 cation channel was discovered by us and others as an essential sensor of mechanical stimuli in several skeletal cell types, such as chondrocytes, osteoblasts and osteocytes. This was illustrated by a large variety of conditional knockout mouse models of Piezo1, that all demonstrated early-onset of osteoporosis with or without multiple fractures, and no longer reacted to mechanical stimuli. These first studies already highlighted a major role of Piezo1 in skeletal growth and disease, but the severity of their phenotypes also hampered the investigation of milder and more translational forms of defects in mechanosensation. The overall aim of the proposed project is therefore to now mimic and characterize induced loss of Piezo1-mediated mechanosensation in vivo at different ages. Therefore, we will investigate mice with inducible knockout of Piezo1 in bone or cartilage tissue in young and aged mice. The aim is to detect general or age-specific effects through in-depth phenotyping of the skeleton of these mice and to identify differences in circulating serum parameters contributing to these phenotypes. The skeleton of inducible knockout mice of Piezo1 in cartilage or bone tissue will be investigated in-depth by combining µCT analysis and histology, by which we will collect information on the structural and cellular properties of the skeleton. Overall, this project will inform us on the age-specific effects of loss of mechanosensation by Piezo1. Moreover, these results will undoubtedly also result in an improved understanding of the acute effects of, for example, a period of immobilization, low physical activity or a space flight on a young or older adult skeleton.

Researcher(s)

Research team(s)

Unraveling the Role of Paraoxonase 1 and 3 in the Etiology and Progression of Obesity and Obesity-Associated Liver Disease 01/11/2020 - 31/10/2022

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)

Research team(s)

The role of the paraoxonase gene family in obesity and obesity-associated liver disease following exposure to environmental pollutants or medical intervention strategies. 01/01/2019 - 31/12/2022

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)

Research team(s)

Gene identification and zebrafish disease modeling of inherited bone disorders 01/01/2017 - 31/12/2021

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)

Research team(s)

Past projects

In vitro studies into the downstream regulatory mechanism whereby LRP4 and sclerostin together regulate Wnt siganling activity. 01/04/2019 - 30/03/2020

Abstract

Previous genetic and functional studies have shown that the canonical Wnt signaling pathway is an important pathway in the regulation of bone formation. The pathway is activated by the binding of Wnt ligands to the receptor complex formed by a Frizzled receptor and an LRP5/6 co-receptor. Furthermore, it is well known that sclerostin is an important inhibitor of the pathway that prevents Wnt ligands from binding to LRP/6 and activating the pathway. Although it is clear that sclerostin can also binds to LRP4 and that this interaction is important for the inhibitory actions of sclerostin, the exact downstream mechanism of this interaction is unclear. In literature, it is reported that LRP4 has an endocytosis signal in its intracellular domain and in addition, several years ago one study demonstrated in murine mesenchymal stem cells that sclerostin is internalized via clathrin dependent endocytosis. Consequently, the aim of this study is to investigate the role of LRP4 in the endocytosis of sclerostin. To do this, primary osteoblasts isolated from the long bones of wild type and Lrp4 mutant mice are treated with fluorescent tagged sclerostin and visualized using fluorescent microscopy. In addition, using different LRP4/5/6 mutant constructs, we aim to further investigate the role of the different receptors in the internalization process. Mutant and wild type constructs will be overexpressed in wild type primary osteoblasts and internalization of fluorescent tagged sclerostin will be evaluated using fluorescent microscopy and western blot. The results of these studies will increase the insights in the downstream mechanisms of the inhibitory action of sclerostin and LRP4. Furthermore, we will evaluate the role of LRP5/6 in this process. Overall we believe that this study will increase the knowledge on the regulation of the canonical Wnt signaling pathway by sclerostin and LRP4 which is important since sclerostin is an important therapeutic target for the treatment of osteoporosis and other bone diseases.

Researcher(s)

  • Promotor: Boudin Eveline

Research team(s)

Functional evaluation of the role of LRP4 and NPR3 in the regulation of bone metabolism by regulating respectively bone mass and bone growth. 01/10/2017 - 30/09/2020

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)

Research team(s)

Study into the role of genetic variation in NPR3 in the regulation of endochondral bone formation and bone growth. 01/04/2017 - 31/03/2018

Abstract

Previous to this study, we identified using whole exome sequencing the first two human mutations in NPR3 in two boys with peculiar phenotype marked by tall stature, arachnodactyly, hypotonia and hyperlaxity of the joints among other features. Based on in silico analysis using SNP databases and prediction programs and based on the available literature regarding NPR3 and the natriuretic signalling pathway, we are convinced that the identified variants are the disease causing variants. However, the exact mechanism whereby the identified mutations result in the observed phenotype remains unknown. During this project, we aim to increase the knowledge on NPR3 and its role in the regulation of bone growth by studying the functional effect of the identified variants in different in vitro assays as well as by screening additional samples with an abnormal growth in height. We are convinced that with the proposed experiments, we will be able to increase the insights on the role of the natriuretic signalling pathway in the regulation of bone growth.

Researcher(s)

  • Promotor: Boudin Eveline

Research team(s)

Paget's disease of bone: molecular genetic investigation of the NFkB signaling regulating genes CBL, CBLB, and NR4A1 and functional validation in vitro and in Danio rerio. 01/01/2017 - 31/12/2020

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)

Research team(s)

Study into the role of NPR3 in the regulation of endochondral bone formation and bone growth. 01/01/2017 - 31/12/2019

Abstract

Preliminary results indicated that loss-of-function mutations in the natriuretic peptide receptor 3 (NPR3) cause tall stature, joint hyperlaxity, hypotonia, aorta dilatation, arachnodactyly, enlarged big toes and extra epiphysis in fingers and toes in two Dutch siblings. NPR3 is a receptor of the natriuretic peptide system that is important for the regulation of bone growth as well as cardiovascular homeostasis. NPR3 is an important regulator of the natriuretic peptide system since it's involved in the clearance of natriuretic peptides and in the regulation of two distinct intracellular signaling cascades. With this project, we aim to investigate the effect of genetic variation in NPR3 on endochondral bone formation and height. This will be studied by screening DNA samples of patients with either a tall or short stature for genetic variation in NPR3. In addition, the effect of the mutations in NPR3 on natriuretic peptide signaling and on bone growth will be studied using different in vitro functional studies. With these studies, we want to confirm the effect of the recently identified mutations and further evaluate the role of NPR3 and the natriuretic peptide signaling pathway in the regulation of bone growth.

Researcher(s)

  • Promotor: Boudin Eveline

Research team(s)

Gα subunits as intracellular partners of WNT16 in osteoblasts – a functional analysis. 26/11/2015 - 31/12/2016

Abstract

Osteoporosis is a skeletal disorder affecting hundreds of millions of people and is characterized by a reduced bone mineral density (BMD) and disruption of the bone micro-architecture, resulting in an increased risk of fragility fractures. Currently, one in three women and one in five men above the age of 50 experience an osteoporotic fracture, making osteoporosis a defining health problem of our ageing society. Hereto, the past decade, numerous candidate gene and genome-wide association studies were performed to identify new, putative therapeutic targets for osteoporosis. Here, WNT16, a modulator of WNT signaling, was discovered to be associated with BMD and fracture risk by several genetic studies. Subsequent in vitro and in vivo functional studies highlight WNT16 as an interesting target for osteoporosis and new treatment strategies targeting the regulation of WNT16 might be useful to reduce fracture risk. Therefore, the general aim of this project is to explain the downstream effects of WNT16 on WNT signaling in osteoblasts. Our preliminary data indicate that WNT16 activates both canonical and non-canonical WNT signaling in osteoblasts, of which activation of canonical WNT signaling occurs in a non-standard manner. The current literature suggests that these preliminary data can be fully explained by the recruitment of specific Gα-subunits to the Frizzled receptor, after WNT16 binding to osteoblasts. This hypothesis will be investigated by performing knockdown of these Gα-subunits in osteoblasts, after which the activity of the different WNT signaling pathways by WNT16 will be monitored. Performing these functional experiments could lead to a better understanding of the effects of WNT16 on osteoblasts. This knowledge can definitely be valuable in the research to new treatment strategies to reduce the risk for osteoporotic fractures in the future.

Researcher(s)

Research team(s)

Identification of a novel disease causing gene for osteopetrosis using next generation sequencing technology. 01/02/2015 - 31/12/2015

Abstract

The osteopetrosis rat is a spontaneously developped rat model for osteopetrosis, a rare bone disorder marked by increased bone density as a result of decreased bone resorption. Previously, we showed that the disease causing gene is located in a 1.36Mb region on rat chromosome 10. Here, we aim to identify the disease causing mutation using NGS technology and we will try to confirm the role of the identified gene in human osteopetrosis patients.

Researcher(s)

  • Promotor: Boudin Eveline

Research team(s)

Study on the role of LRP4 in the regulation of Wnt signaling and bone formation. 01/01/2015 - 31/12/2018

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)

Research team(s)

The role of adiponutrin (PNPLA3) in the pathogenesis of hepatosteatosis as part of the metabolic syndrome 01/02/2014 - 30/11/2014

Abstract

Non-alcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease worldwide. A genetic basis for the disease has been suggested, but only few causal genes have been identified. In the proposed project we aim to further evaluate the involvement of PNPLA3 in NAFLD through genetic mutation analysis and analysis of its biological function in a human liver cell line.

Researcher(s)

  • Promotor: Zegers Doreen

Research team(s)

Systems biology for the functional validation of genetic determinants of skeletal diseases (SYBIL). 01/10/2013 - 30/09/2018

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)

Research team(s)

Evaluation of the role of LRP4 in the regulation of Wnt/Bcatenin dependent Wnt signalling and bone formation. 01/10/2013 - 30/09/2016

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)

Research team(s)

The role of the PREPL gene in the development of obesity. 01/02/2013 - 31/12/2013

Abstract

Obesity is currently one of the most prevalent diseases worldwide. Genetic research has already identified several genetic variants that contribute to the development of the disease. However, these variants currently only explain about 1.5% of variance in BMI, demonstrating that a large number of the genetic factors involved remain unknown. Research into structural variations can possibly identify new candidate genes that can contribute to this so-called "missing heritability". Previous research from our group has identified a microdeletion containing the PREPL gene in an obese patient, indicating that this gene might be important in the pathophysiology of obesity. Therefore, we aim to study the role of PREPL in obesity further in the current research proposal through screening of a large population of obese children and adolescents, as well as a group of healthy, lean subjects, in search of additional carriers of the PREPL-containing deletion and carriers of loss-of-function mutations in this gene. With this research, we will therefore be able to contribute considerably to the knowledge about the development of obesity.

Researcher(s)

Research team(s)

Genetic analysis of five candidate genes in the pathogenesis of obesity. 01/01/2013 - 31/12/2016

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)

Research team(s)

Identification and characterization of the gene underlying hyperostosis cranialis interna. 01/01/2012 - 31/12/2015

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)

Research team(s)

Genetic and functional study of LRP4 and the R-spondins in bone formation. 01/01/2012 - 31/12/2015

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)

Research team(s)

Genetic and functional study of the effect of sclerostin-binding proteins on bone anabolism. 01/10/2011 - 31/12/2011

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)

Research team(s)

Positional cloning of two genes responsible for an abnormal bone density. 01/01/2011 - 31/12/2012

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)

Research team(s)

Genetic analysis of the role of sFRP1 and 4 in the bone homeostasis. 01/01/2011 - 31/12/2012

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)

Research team(s)

Molecular genetic and functional analysis of the role of Wnt signaling in the pathogenesis of osteoporosis and obesity. 01/01/2010 - 31/12/2013

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)

Research team(s)

Genetic and functional analysis of two genes underlying an osteopetrotic rat model (incisors absent and osteopetrotic). 01/01/2010 - 31/12/2013

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)

Research team(s)

Genetic study of the melanocortin signal transduction in the pathogenesis of obesity. 01/01/2010 - 31/12/2011

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)

Research team(s)

Research into the role of resistin in the pathogenesis of obesity and osteoporosis. 01/10/2009 - 30/09/2013

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)

Research team(s)

Research into basic or clinical aspects of bone metabolism. 09/06/2008 - 08/06/2011

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)

Research team(s)

Targeting LRP5 to increase bone formation in osteoporosis (TALOS). 01/05/2008 - 30/04/2011

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)

Research team(s)

Genetic study of the melanocortin signal transduction in the pathogenesis of obesity. 01/01/2008 - 31/12/2009

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)

Research team(s)

Functional analysis of the role of secreted Frizzled-related proteins in bone metabolism. 01/07/2007 - 31/12/2011

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)

Research team(s)

Genetic study of obesity and associated insulin resistance. 01/01/2007 - 31/12/2008

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)

Research team(s)

Study into the role of the protein plekhm1 in the deterioration of bone tissue. 01/12/2006 - 30/09/2008

Abstract

Researcher(s)

  • Promotor: Van Wesenbeeck Liesbeth

Research team(s)

Study of genetic variants in genes from the Wnt signaling pathway in the regulation of peak bone miral density. 01/10/2006 - 15/09/2007

Abstract

The general objective of this project is to contribute to the understanding of the genetic regulation of peak BMD (pBMD) in the general population and to understand the pathogenesis of osteoporosis. We will focus on a number of genes known to modulate canonical Wnt signaling. Association analyses in a well-characterized, Danish cohort of young men will be carried out to evaluate the role of four extracellular modulators of Wnt signal transduction (Dkk1, Dkk2, sFRP1 and SOST) as susceptibility genes in the regulation of pBMD. Once we identified a gene that is associated with pBMD, we will search for the causative variant. Studies will consequently be carried out to unravel the functional relevance of this causative variant.

Researcher(s)

  • Promotor: Balemans Wendy

Research team(s)

Identification of the gene responsible for the osteopetrotic (op) ratmodel. 01/03/2006 - 31/12/2007

Abstract

This project aims the identification of the gene responsible for the osteopetrotic phenotype of the spontaneous osteopetrotic ratmodel. The role of this gene in human osteopetrosis will also be evaluated. This research project has the potential to identify a new gene involved in bone metabolism and this will undoubtly lead to a better understanding of bone resorption.

Researcher(s)

  • Promotor: Van Wesenbeeck Liesbeth

Research team(s)

Functional characterization of genes involved in bone formation and bone resorption. 01/01/2006 - 31/12/2009

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)

Research team(s)

Implementation of non-viral transfection technology for osteoclasts in the functional characterization of the plekhm 1 gene. 01/01/2006 - 30/09/2008

Abstract

Gelieve aan te vullen a.u.b.

Researcher(s)

  • Promotor: Van Wesenbeeck Liesbeth

Research team(s)

Functional characterization of the gene responsicle for the osteopetrotic phenotype of the incisors absent rat. 01/10/2005 - 30/09/2008

Abstract

Researcher(s)

Research team(s)

Functional studies of two putatively interacting metabolic pathways active in bone formation. 01/10/2005 - 15/09/2007

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)

Research team(s)

Characterization of the recently identified gene underlying the osteopetrotic "Incisors Absent" ratmodel. 01/05/2005 - 30/04/2009

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)

Research team(s)

Introduction of methods for cultivation and phenotypic characterization of primary osteoclasts and osteoblasts. 01/05/2005 - 31/12/2006

Abstract

The aim of this project is to introduce some of the basic methodologies indispensable in the field of bone research. On the one side, this will include cultivation of osteoclasts and osteoblasts starting from respectively human peripheral blood and RAW264.7 cells, and human bone fragments. On the other side, methods will be optimized to phenotypically characterize these cell types allowing us to study cell differentation and functional activity. These techniques will enable us to functionally characterize recently identified genes.

Researcher(s)

  • Promotor: Balemans Wendy

Research team(s)

Genetic study of obesity and associated insulin resistance. 01/01/2005 - 31/12/2006

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)

Research team(s)

Genetic association studies for Paget's disease of bone. 01/01/2005 - 31/12/2005

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)

Research team(s)

Study of a possible interaction between two metabolic pathways important for the production of the bone tissue. 01/12/2004 - 31/12/2006

Abstract

Researcher(s)

  • Promotor: Balemans Wendy

Research team(s)

Further characterisation of the role of TGF-beta1 in bone metabolism and identification of currently unknown genes involved in osteoblast differentiation. 01/10/2004 - 30/09/2007

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.

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Elucidation of the biological function of sclerostin - a bone formation inhibitor - by studying transcriptional regulation and interaction with Wnt signal tranduction. 01/10/2004 - 30/09/2005

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.

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Molecular mechanisms of bone formation and anabolism.(ANABONOS) 01/03/2004 - 31/08/2007

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.

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Genetic Markers for Osteoporosis (GENOMOS). 01/01/2003 - 31/12/2006

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.

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Identification and characterization of genes responsible for osteopetrosis. 01/01/2003 - 31/12/2004

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.

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Functional analysis of the EXTL1 gene as a putative tumor suppressor gene. 01/01/2002 - 31/12/2003

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.

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Genetic association studies in osteoporosis with candidate genes. 01/01/2001 - 31/12/2004

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.

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Identification of genes involved in rheumatic conditions. 01/01/2000 - 31/12/2005

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.

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