Src Regulation of Lung Endothelial Barrier Function

Src 对肺内皮屏障功能的调节

基本信息

批准号：
8434033
负责人：
RICHARD D MINSHALL
金额：
$ 31.95万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8434033
关键词：
1-Phosphatidylinositol 3-Kinase Address Adhesions Adult Respiratory Distress Syndrome Affinity Albumins Binding Biochemical Blood Vessels Caveolae Cell membrane Cellular biology Coupling Data Dynamin 2 Edema Endothelial Cells Event Gene Deletion Goals Image Inflammatory Inflammatory Response Intercellular adhesion molecule 1 Lead Lung Mediating Modification Mus Oxidants PTPN11 gene Pathway interactions Permeability Phosphatidylinositols Phosphorylation Physiological Post-Translational Protein Processing Protein Biosynthesis Protein Dephosphorylation Protein Kinase Protein Tyrosine Phosphatase Pulmonary Circulation Pulmonary Edema Pulmonary vessels Recruitment Activity Regulation Role Secondary to Signal Pathway Signal Transduction Signal Transduction Pathway Site Testing Time Translations base caveolin 1 cytokine feeding filamin lung injury lung vascular injury molecular imaging neutrophil new therapeutic target novel protein kinase C zeta transcytosis uptake

项目摘要

In Project 4, we will test the hypotheses that (i) Nox2-dependent oxidant signaling activates Src kinas dependent ICAM-1-phosphorylation and thereby the recruitment of PMNs in the pulmonary circulation, and that (ii) Src phosphorylation of ICAM-1 in turn protracts Src activation and phosphorylation of caveolin-1 and dynamin-2, thereby triggering caveolae-mediated transcytosis of albumin and endothelial hyper-permeability. These studies will address the following Specific Aims: (1) role of PI3-kinase, PKC zeta, Nox2, and Src signaling, and of Akt phosphorylation of filamin A in the mechanism of ICAM-1 phosphorylation, clustering, and rapid increase in ICAM-1 binding affinity in lung microvascular endothelial cells and PMN uptake in lungs; (2) role of phospho-ICAM-1 in recruitment of SHP2 and protracting Src activation and thereby caveolin-1 and dynamin-2 activation, and thus stimulating caveolae-mediated transcytosis and hyper-permeability of albumin. Project 4 will delineate the signaling mechanisms mediating the post-translational modification of ICAM-1 in pulmonary microvessel endothelial cells using imaging, cell biology, biochemical, and physiological approaches. We will thereby establish how endothelial cell ICAM-1 shifts to a high-affinity state and promotes PMN adhesion and sequestration and also induces caveolae-mediated hyper-permeability via the transcytosis of albumin. These studies it is hoped will lead to a new understanding of the early PMN-mediated lung inflammatory response and its coupling to lung vascular hyper-permeability. Identification of the key signaling hubs of ICAM-1-mediated endothelial adhesivity and activation of the caveolae-mediated albumin transport pathway is likely to provide novel therapeutic targets directed against inflammatory lung injury.

在项目 4 中，我们将测试以下假设：(i) Nox2 依赖性氧化剂信号传导激活 Src 激酶依赖性 ICAM-1 磷酸化，从而在肺循环中募集 PMN，以及 (ii) ICAM-1 的 Src 磷酸化转延长了 Caveolin-1 和 dynamin-2 的 Src 激活和磷酸化，从而触发 Caveolae 介导的白蛋白和内皮细胞转胞吞作用超渗透性。这些研究将解决以下具体目标：(1) PI3 激酶、PKC zeta、Nox2 和 Src 信号传导以及细丝蛋白 A 的 Akt 磷酸化在 ICAM-1 磷酸化、聚类和 ICAM 快速增加机制中的作用-1 肺微血管内皮细胞的结合亲和力和肺中 PMN 的摄取； (2)磷酸-ICAM-1在SHP2募集和延长Src激活中的作用，从而激活caveolae-1和dynamin-2，从而刺激caveolae介导的转胞吞作用和白蛋白的高渗透性。项目 4 将利用成像、细胞生物学、生化和生理学方法描述介导肺微血管内皮细胞中 ICAM-1 翻译后修饰的信号传导机制。因此，我们将确定内皮细胞 ICAM-1 如何转变为高亲和力状态并促进 PMN 粘附和隔离，并通过白蛋白的转胞吞作用诱导小凹介导的高通透性。希望这些研究能够使人们对早期 PMN 介导的肺部炎症反应及其与肺血管高渗透性的耦合产生新的认识。鉴定 ICAM-1 介导的内皮粘附性和小窝介导的白蛋白转运途径激活的关键信号中枢可能会提供针对炎症性肺损伤的新治疗靶点。