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：
8059132
负责人：
RICHARD D MINSHALL
金额：
$ 33.47万
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：
2011
资助国家：
美国
起止时间：
2011-03-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8059132
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 kinasedependent 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-translafional 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 infiammatory lung injury.

在项目 4 中，我们将测试以下假设：(i) Nox2 依赖性氧化信号激活 Src 激酶依赖性 ICAM-1 磷酸化，从而在肺循环中募集 PMN，并且 (ii) ICAM-1 的 Src 磷酸化反过来又延长了 Caveolin-1 的 Src 激活和磷酸化， dynamin-2，从而触发小窝介导的白蛋白转胞吞作用和内皮细胞通透性过高。这些研究将解决以下具体目标：(1) PI3 激酶、PKC zeta、Nox2 和 Src 的作用 ICAM-1 磷酸化、聚类和机制中 Filamin A 的 Akt 磷酸化肺微血管内皮细胞中 ICAM-1 结合亲和力和肺中 PMN 摄取迅速增加； (2) 磷酸化 ICAM-1 在 SHP2 募集和延长 Src 激活中的作用，从而延长 Caveolin-1 和 dynamin-2 激活，从而刺激小窝介导的转胞吞作用和白蛋白的高渗透性。项目 4 将描述介导 ICAM-1 翻译后修饰的信号机制利用成像、细胞生物学、生化和生理学研究肺微血管内皮细胞接近。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，还通过转胞吞作用诱导小凹介导的高通透性白蛋白。希望这些研究能够带来对早期 PMN 介导的肺的新认识炎症反应及其与肺血管高渗透性的耦合。关键信号的识别 ICAM-1 介导的内皮粘附性和小窝介导的白蛋白转运激活的中枢途径可能提供针对炎症性肺损伤的新治疗靶点。