Microfibrils in Vascular Morphogenesis and Disease

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Development of effective therapies to counteract the devastating effects of extracellular matrix deficiencies on organismal development and function remains a formidable challenge. Our recent studies using mouse models of Marfan Syndrome (MFS) have raised the possibility of utilizing novel biological targets for MFS therapy. It is precisely the scope of this Program Project to explore further this possibility and advance our understanding of microfibril pathophysiology, with the idea of translating this information into productive clinical applications in MFS. Project1 focuses on the study of the etiopathogenesis of aortic dissection, the leading cause of mortality in the MFS. Specifically, we propose to characterize the molecular mechanisms and cellular factors that predispose the fibrillin-1-deficient wall of the ascending aorta to structural collapse. Our underlying hypothesis is that fibrillin-1 mutations in MFS cause a complex pathogenetic sequence that includes loss of tissue integrity, dysregulated cellular activities, and perturbed growth factor signaling. The proposed studies will be performed on genetically engineered mouse models that faithfully replicate the clinical spectrum of MFS using state-of-the-art technologies. Three aims will be pursued. The first aim employs DNA microarray and cell culture experiments to identify information molecular and cellular events responsible for aneurysm formation and progression in our mouse models of MFS. The second aim exploits genetic combinations of fibrillin-1 and fibrillin-2 null alleles to elucidate the full range of contributions of the extracellular microfibrils to arterial morphogenesis and homeostasis. The third aim proposes to create a new strain of mutant mice in which fibrillin-1 can no longer bind LTBP1 in order to determine the functional relationship between matrix sequestration of latent TGFbeta and growth factor signaling in the developing and mature aorta. These aims are conceptually and experimentally inter-related with the other components of the PO1. Most importantly, the investigations of Project 1 will be instrumental in guiding the development of rational drug-based treatments of dissecting aneurysm in MFS.