S1P/Rac Regulation of Endothelial Cell Permeability

描述（由申请人提供）：内皮细胞（EC）在血液和底层组织间质之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，可见于炎症、肿瘤血管生成和动脉粥样硬化。因此，增强EC屏障功能的药物可用于治疗多种疾病。鞘氨醇-1-磷酸（S1P）是一种血小板来源的脂质，对内皮细胞有许多重要作用，包括促进屏障功能的增强，这依赖于S1P与其主要细胞表面受体S1P受体的结合，以及小GTPase Rac1的激活。本项目旨在阐明S1P调控Rac1信号、随后的下游效应物和皮质肌动蛋白（一种肌动蛋白结合蛋白）易位的机制，因为它们与皮质肌动蛋白细胞骨架重排和内皮细胞屏障功能增强有关。Specific Aim #1聚焦于s1p介导的EC中Rac1激活的表征。特异性目标#2侧重于从机制上描述EC中S1P治疗后rac介导的皮质肌动蛋白重排。特异性目标#3侧重于表征EC中S1P治疗后rac介导的接触蛋白相互作用。

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.