S1P/Rac Regulation of Endothelial Cell Permeability

描述（由申请方提供）：内皮细胞（EC）在血液和下层组织间提供半选择性屏障。这种屏障的破坏导致血管通透性增加，如在炎症、肿瘤血管生成和动脉粥样硬化中所见。因此，增强EC屏障功能的药剂可以治疗多种疾病。鞘氨醇-1-磷酸（S1 P）是一种血小板衍生的脂质，对EC具有许多重要作用，包括促进依赖于S1 P与其主要细胞表面受体S1 P受体结合的屏障功能增加，以及小GT3 Rac 1的活化。本项目拟阐明Rac 1信号的S1 P调节机制，随后的下游效应器和corpine（肌动蛋白结合蛋白）易位，因为它们与皮质肌动蛋白细胞骨架重排和增加内皮细胞屏障功能有关。具体目标#1侧重于EC中S1 P介导的Rac 1活化的表征。Specific Aim #2侧重于从机制上描述EC中S1 P治疗后Rac介导的皮质肌动蛋白重排。具体目标#3侧重于表征EC中S1 P处理后Rac介导的coronin蛋白相互作用。

DESCRIPTION (provided by applicant): Endothelial cells (EC) provide a semi-selective barrier between the blood and underlying tissue interstitium. Disruption of this barrier results in increased vascular permeability as seen in inflammation, tumor angiogenesis and atherosclerosis. Therefore, agents that enhance EC barrier function can be therapeutic for a variety of diseases. Sphingosine-1-phosphate (S1P) is a platelet-derived lipid that has many important effects on ECs including promoting increased barrier function that is dependent on S1P binding to its major cell surface receptor, S1P receptor, and activation of the small GTPase Rac1. This project proposes to elucidate the mechanism(s) of S1P regulation of Rac1 signaling, consequent downstream effectors and cortactin (an actin binding protein) translocation as they relate to cortical actin cytoskeletal rearrangement and increased endothelial cell barrier function. Specific Aim #1 focuses on characterization of S1P-mediated Rac1 activation in EC. Specifc Aim #2 focuses on mechanistically describing Rac-mediated cortical actin rearrangement after S1P treatment in EC. Specifc Aim #3 focuses on characterizing Rac-mediated cortactin protein interactions after S1P treatment in EC.