Project Summary Marfan Syndrome (MFS) is a genetic disorder of the connective tissue caused by mutations in the fibrillin- 1(FBN1) gene. These mutations cause increased vascular smooth muscle cell (vSMC) apoptosis, increased matrix metalloproteinase (MMP) expression, excessive elastin degeneration and collagen overexpression; weakening the vascular architecture, impair hemodynamic regulation, and ultimately leading to severe vascular complications. Primary cells, tissue explants, and transgenic mouse models suffer from insufficiencies that inhibit development of novel insights into disease pathogenesis or potential therapeutics; warranting new modeling platforms. Recent advances in biomaterials have generated vascular grafts that mimic properties of the extracellular matrix (ECM) in the natural vasculature. Human induced pluripotent stem cells (hiPSC) are an ideal, patient specific renewable cell source that provides an avenue to study how genetic diseases effect cell mechanobiology, signaling and function to better development therapeutics. Here, using a natural fibrin-based vascular graft and hiPSCs from patients with Marfan Syndrome, we aim to: (1) fully characterized both ECs and contractile vSMCs from hiPSCs derived from Marfan patients, (2) study the responses of hiPSC-ECs to shear force and hiPSC-vSMCs to circumferential strain, (3) study the impacts of mechanical forces (i.e. shear force and circumferential strain) and paracrine signaling in a co-culture model, specifically reactive oxygen species(ROS), on vSMC phenotype and rate of graft degradation using the fibrin-based vascular graft. Our multidisciplinary approach underpinning this project will elucidate key mediators of MFS disease progression towards early detection and therapeutic targets.