S1P/Rac Regulation of Endothelial Cell Permeability

S1P/Rac 对内皮细胞通透性的调节

• 批准号: 6885161
• 负责人: Patrick A Singleton
• 金额: $ 4.4万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6885161
• 关键词: Adenoviridae; actin binding protein; biological signal transduction; dynamin; endocytosis; enzyme activity; enzyme mechanism; guanine nucleotide binding protein; guanine nucleotide exchange factors; guanosinetriphosphatases; human tissue; immunoprecipitation; mass spectrometry; phosphates; postdoctoral investigator; protein protein interaction; proteomics; pulmonary artery; serine threonine protein kinase; small interfering RNA; sphingosine; tissue /cell culture; transfection /expression vector; vascular endothelium permeability

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.

描述（由申请人提供）：内皮细胞（EC）在血液和下面的组织间质之间提供半选择性屏障。该屏障的破坏会导致血管通透性增加，如炎症、肿瘤血管生成和动脉粥样硬化所示。因此，增强EC屏障功能的药物可以治疗多种疾病。 1-磷酸鞘氨醇 (S1P) 是一种血小板衍生的脂质，对 EC 有许多重要作用，包括促进屏障功能的增强，该功能依赖于 S1P 与其主要细胞表面受体 S1P 受体的结合，以及小 GTP 酶 Rac1 的激活。该项目旨在阐明 Rac1 信号传导、后续下游效应器和皮质肌动蛋白（肌动蛋白结合蛋白）易位的 S1P 调节机制，因为它们与皮质肌动蛋白细胞骨架重排和增强的内皮细胞屏障功能有关。具体目标#1 侧重于 EC 中 S1P 介导的 Rac1 激活的表征。具体目标#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。具体目标 #3 侧重于表征 EC 中 S1P 处理后 Rac 介导的皮质蛋白相互作用。