Analysis of PECAM-1-dependent mechanotransduction in endothelial cells

身体上的压力会导致许多疾病，如动脉粥样硬化。然而，细胞机械转导的分子机制，即细胞感知和响应机械信号的过程，在很大程度上仍然未知。动脉粥样硬化斑块优先发生在血管分支或弯曲部位的低血流量区域。这些区域复杂的血流刺激内皮细胞的炎症信号通路，从而引发动脉粥样硬化。PECAM-1最近被确定为一种机械反应蛋白，对剪切力的感知和传递至关重要，因此与动脉粥样硬化的发生有关。在这里，我建议研究PECAM-1依赖性机械转导的分子机制。我将研究PECAM-1突变对细胞对流体剪切应力反应的影响。基于这些结果，我们将进一步分析所涉及的效应分子的作用。最后，我将研究PECAM-1使用可拉伸基板或磁珠的直接力传导。

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.