Regulation of NADPH Oxidase by Phospholipase D and the EC Cytoskeleton

磷脂酶 D 和 EC 细胞骨架对 NADPH 氧化酶的调节

基本信息

批准号：
8214990
负责人：
VISWANATHAN NATARAJAN
金额：
$ 30.06万
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：
2011-02-01 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8214990
关键词：
Actins Actomyosin Acute Lung Injury Adaptor Signaling Protein Address Adherens Junction Adhesives Agonist Alveolar Animal Model Area Binding Biological Assay Biology Blood Vessels Blood capillaries Blood gas Cell Adhesion Cell Culture Techniques Cell membrane Cells Chemicals Co-Immunoprecipitations Collaborations Complex Cytoskeletal Modeling Cytoskeleton Data Down-Regulation Elements Endothelial Cells Endothelium Ensure Environment Environmental air flow Epithelial Equilibrium Exhibits Floods Focal Adhesions Functional disorder GIT2 gene Gel Genetic Polymorphism Guanosine Triphosphate Phosphohydrolases Hepatocyte Growth Factor Human Human Resources Hypoxemia Image Imaging Techniques In Vitro Infiltration Inflammation Inflammatory Injury Knock-out Knockout Mice Leukocytes Liquid substance Lung Maintenance Mechanical Stress Mechanical ventilation Mechanics Mediating Microfilaments Modeling Molecular Monomeric GTP-Binding Proteins Morbidity - disease rate Mus Myosin Light Chain Kinase NADP NADPH Oxidase Names Pathogenesis Pathologic Pathway interactions Patients Pattern Peptides Peripheral Permeability Phospholipase D Phosphorylation Phosphorylcholine Physiological Principal Investigator Process Production Property Protein Isoforms Proteins Publishing Pulmonary Circulation Pulmonary artery structure Reactive Oxygen Species Reagent Regimen Regulation Research Personnel Resolution Resources Role Scaffolding Protein Scientist Signal Transduction Stimulus Stretching Syndrome Techniques Tertiary Protein Structure Testing Thrombin Tidal Volume Tight Junctions Time Transfection Variant Vascular Endothelial Growth Factors Vascular Permeabilities Ventilator-induced lung injury attenuation capillary cytokine human EMS1 protein in vivo insight mortality mutant new technology novel overexpression paxillin programs protective effect response rho shear stress sphingosine 1-phosphate synergism

项目摘要

Compromise of the pulmonary endothelial cell (EC) barrier is induced by mechanical stress which is associated with ventilator-induced lung injury (VILI), This process leads to increased vascular permeability, alveolar flooding, leukocyte infiltration, hypoxemia, and increased morbidity and mortality. Project #3 scientists have previously identified cytoskeletal mechanisms of EC barrier regulation by barrier-protective strategies (oxidized phosphocholine, sphingosine 1-phosphate, physiologic shear stress and cyclic stretch (CS) and barrier-disruptive mechanical and chemical stimuli (thrombin, pathologic CS). In addition, these PPG investigator have described the critical involvement of small GTPases Rac and Rho in remodeling of EC cytoskeleton and cell contacts essential for EC barrier regulation. Our published results and preliminary data strongly suggest that magnitude-dependent modulation of Rac and Rho activities by CS significantly impacts agonist-induced EC permeability changes. The Project #3 hypothesis is that pathologic CS and vascular endothelial growth factor (VEGF), known to be elevated during VILI, promote lung endothelial barrier dysfunction via synergistic effects on Rho pathway-mediated EC permeability. These processes are counterbalanced by Rac-dependent mechanisms induced by barrier-protective stimuli such as hepatocyte growth factor (HGF) and physiologic stretch. We speculate that focal adhesions may act as mechanosensors and modulate small GTPase activities via specific paxillin interactions with Rac and Rho protein regulators. Specific Aim #1 will study synergistic effects between pathologic CS and VEGF on activation of Rhomediated EC barrier dysfunction. Specific Aim #2 will define barrier-protective strategies in amelioration of VILI-associated EC barrier dysfunction via changes in a balance between the Rho and Rac activities. Specific Aim #3 will study novel mechanisms of Rac/Rho regulation by mechanochemical factors via interactions between wild type paxillin (or/and paxillin containing the Gly73Ser polymorphism) interactions with modulators of Rac and Rho activity (GIT2, betaPIX, PAK1 and p190RhoGAP). These studies will uncover novel molecular mechanisms involved in the pathogenesis and resolution of ventilator-induced lung injury.

肺内皮细胞（EC）屏障的妥协是由机械应力引起的，与呼吸机诱导的肺损伤（VILI）相关，此过程导致血管通透性增加，肺泡洪水，白细胞浸润，低氧血症以及发病率和死亡率增加。项目＃3 科学家以前已经确定了通过屏障保护的EC屏障调节的细胞骨架机制策略（氧化的磷胆碱，1-磷酸盐，生理剪切应力和环状拉伸（CS）和屏障干扰性的机械和化学刺激（凝血酶，病理CS）。另外，这些 PPG研究者描述了小型GTPases RAC和RHO在重塑中的关键参与 EC细胞骨架和细胞接触对于EC屏障调节必不可少的。我们发表的结果和初步数据强烈表明，CS对RAC和RHO活动的幅度依赖性调制影响激动剂引起的EC渗透性变化。项目＃3假设是病理CS和血管内皮生长因子（VEGF）已知在VILI期间升高，促进肺部内皮通过对RHO途径介导的EC渗透性的协同作用的屏障功能障碍。这些过程是由屏障保护刺激（例如肝细胞）引起的RAC依赖机制的平衡生长因子（HGF）和生理拉伸。我们推测焦点粘连可能充当机械传感器并通过特异性的帕克西林与RAC和RHO蛋白调节剂进行调节小型GTPase活性。特定的目标＃1将研究病理CS和VEGF之间的协同作用对综艺的激活 EC屏障功能障碍。特定目标＃2将定义屏障保护策略 VILI相关的EC屏障功能障碍通过RHO和RAC活动之间的平衡发生变化。特定目的＃3将通过机械化学因素研究RAC/RHO调节的新型机制野生型帕克西林（OR/和含有Gly73ser多态性的Paxillin）相互作用之间的相互作用之间的相互作用与RAC和RHO活动的调节剂（Git2，Betapix，Pak1和P190Rhogap）。这些研究会揭示了与呼吸机诱导的肺的发病机理和分辨率有关的新型分子机制受伤。