Unravelling the paradigm of opposing FBN1 phenotypes to identify new pathomechanisms involved in thoracic aortic aneurysms and dissections.

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.

Keywords:AORTA, VASCULAR RESEARCH

Disciplines:Cell signalling, Cellular interactions and extracellular matrix, Vascular diseases