Research Silke Peeters

Abstract

Chondrodysplasias are skeletal disorders attributed to primary defects in hyaline cartilage. Disease severity differs considerably between subtypes, with some only inflicting joint abnormalities and others causing severe dwarfism or perinatal lethality. For many (severe) chondrodysplasias satisfactory therapies are lacking, prompting further research in the underlying disease mechanisms. Endoplasmatic reticulum (ER) stress, and the accompanying excess in chondrocyte apoptosis, have emerged as credible pathomechanisms in some chondrodysplasias, including COL2-pathies. In these conditions chaperone-oriented therapy represents an interesting pharmacological avenue. In this project, we will use iPSC-chondrocyte models to investigate whether ER stress and unfolded protein response (UPR) activation play a role in the etiology of BGN-related chondrodysplasia, which is a pathomechanistically unexplored form of serious dwarfism. IPSC-chondrocytes of patients suffering from severe but non-lethal COL2A1-related spondyloepiphyseal dysplasia congenita will be used as positive controls. Next, we will develop a novel iPSC-chondrocyte-based high-throughput microscopic high content assay, which will be used to pinpoint novel drug candidates (compound library screening) or existing drugs (repurposing) promoting protein folding in ER stress-related chondrodysplasias.

Researcher(s)

• Promoter: Verstraeten Aline
• Co-promoter: Peeters Silke

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

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

Researcher(s)

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

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

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

Researcher(s)

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

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

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

Researcher(s)

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

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

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

Researcher(s)

• Promoter: Peeters Silke

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project