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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(i) nox2依赖的氧化信号激活Src激酶依赖的假设