血流剪应力受体GPR68在缺血性心血管疾病中的调节作用和分子机制

心血管疾病是目前导致全球人口死亡最多的疾病。机体中血液流动产生的剪应力在心血管疾病的病理生理过程起至关重要的作用。在前期研究中，我们发现并鉴定了一个全新的血流感应受体GPR68。GPR68是一个对流体剪应力敏感的G蛋白偶联受体，在小动脉内皮细胞上特异表达，并可以将血流剪应力转化为钙离子信号，由此调节小动脉舒张。此外，GPR68在对血流介导的血管外向重塑也有重要的调节作用。然而，GPR68感知血流速度并调节侧支血管重塑和生长的分子调控机制依然不清晰。本课题计划以小动脉内皮细胞为切入点，分析GPR68感受血流剪应力的信号转导以及激活侧枝血管重塑和生长的通路，并在小鼠缺血性疾病模型中探索GPR68对血流介导的血管外向重塑和侧支血管生长的作用，最终探索GPR68小分子激动剂作为治疗缺血性心血管疾病新策略的可行性。

Cardiovascular diseases is the leading cause of death around the world. The mechanical forces caused by the blood flow is instrumental in the pathophysiology of many cardiovascular diseases. Previously, we have identified a novel blood flow sensor GPR68. GPR68 is a G-protein coupled receptor that is sensitive to fluid shear stress generated by the blood flow. GPR68 is expressed on the plasma membrane of the endothelial cells of arterioles, and is capable to convert shear stress to calcium signals, which in turn regulates flow-mediated dilation of the arterioles. Furthermore, we showed that GPR68 is crucial in flow-mediated outward remodeling of arteriole in vivo. However, the molecular mechanism of GPR68’s function in flow-mediated collateral vessel remodeling and growth is not well understood. We propose to characterize the molecular signaling pathway of GPR68 in the context of arteriole endothelial cells in depth. We will further evaluate the effect of modulating GPR68 activity in rodent models of ischemic diseases, and finally explore the feasibility of utilizing small molecule GPR68 agonist as a new therapeutic strategy for ischemic cardiovascular diseases.