Analysis of PECAM-1-dependent mechanotransduction in endothelial cells

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Physical stress contributes to many diseases such as atherosclerosis. However, the molecular mechanisms of cellular mechanotransduction, the process by which cells sense and respond to mechanical signals, are still largely unknown. Atherosclerotic plaques occur preferentially in regions of low, disturbed blood flow at sites of vessel branching or curvature. The complex blood flow in these areas stimulates inflammatory signalling pathways in endothelial cells, which initiate atherogenesis. PECAM-1 was recently identified as a mechanoresponsive protein that is essential for the sensing and transmission of shear forces and hence was implicated in the initiation of atherosclerosis. Here, I propose to investigate the molecular mechanism of PECAM-1- dependent mechanotransduction. I will examine effects of mutations in PECAM-1 on cellular responses to fluid shear stress. Based on these results, the role of the implicated effector molecules will be further analyzed. Finally, I will investigate direct force transduction by PECAM-1 using stretchable substrates or magnetic beads.