Role of End Binding 3 in Mechanism of vascular permeability

末端结合3在血管通透性机制中的作用

基本信息

批准号：
8207911
负责人：
Yulia A Komarova
金额：
$ 39.25万
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 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8207911
关键词：
Actins Address Adhesions Adult Respiratory Distress Syndrome Affinity Agonist Binding Binding Proteins Biochemical Blood Vessels Calcineurin Calmodulin Cell Shape Cells Complex Cytoskeleton Data Development Down-Regulation Edema Endoplasmic Reticulum Endothelium Event Exhibits Extravasation Functional disorder Gases Gene Transfer Genetic Growth Homeostasis Hypoxemia Image Impairment Inflammation Inflammation Mediators Inflammatory Inositol Life Liquid substance Lung Lung Inflammation Maintenance Mediating Microtubules Modeling Molecular Mus Myosin Light Chain Kinase Pathway interactions Peptides Permeability Phosphorylation Phosphorylation Inhibition Physiological Plasma Plus End of the Microtubule Protein Kinase C Protein Serine/Threonine Phosphatase Proteins Pulmonary Edema Regulation Role SRC gene Sepsis Signal Transduction Stimulus Technology Testing Therapeutic Time Tissues Vascular Permeabilities Work base cadherin 5 cellular imaging design expectation insight mutant novel novel therapeutics prevent receptor response

项目摘要

Increases in lung vascular permeability result in protein-rich tissue edema, an important feature of adult respiratory distress syndrome. The role of the microtubule (MT) cytoskeleton in the mechanism of increased endothelial permeability is not well understood. MTs are known to undergo re-organization in response to pro- inflammatory mediators, and may thus contribute to the mechanism of increased endothelial permeability. The proposed studies will address the central role of End Binding protein-3 (EB3), a MT plus-end binding factor, in regulating increased lung vascular permeability. We will test the hypotheses that (i) EB3 is a major component of cross-talk between Vascular Endothelial (VE)-cadherin adhesion complexes and the MT cytoskeleton and (ii) EB3-mediated control of MT dynamics is critical for maintenance of basal permeability of lung microvessels and for permeability increase caused by inflammatory mediators. These studies will address the following Specific Aims: (1) role of VE-cadherin-mediated signaling in the mechanism of EB3 phosphorylation and inhibition of MT growth and, thereby the role of "outside-in" signaling in establishing basal permeability of lung endothelia; and (2) critical role of EB3 in regulating Ca2+ signaling, thus in mediating increased endothelial permeability and development of lung edema. It is our expectation that by understanding how VE-cadherin adhesion signals EB3 phosphorylation and how EB3 thereby elicits the barrier permeability increase will provide novel insights into the mechanisms of dysregulation of lung fluid homeostasis. We will exploit state of the art technologies including live cell imaging, expression of mutant constructs, gene transfer, and murine models of lung inflammation to accomplish the specific aims.

肺血管通透性增加导致富含蛋白质的组织水肿，这是成人的一个重要特征呼吸窘迫综合征。微管（MT）细胞骨架在增加机制中的作用内皮细胞的通透性尚不清楚。众所周知，MT 会进行重组以应对亲炎症介质，因此可能有助于内皮通透性增加的机制。这拟议的研究将解决末端结合蛋白 3 (EB3)（一种 MT 加末端结合因子）在调节肺血管通透性增加。我们将测试以下假设：(i) EB3 是主要组成部分血管内皮 (VE)-钙粘蛋白粘附复合物和 MT 细胞骨架之间的串扰 (ii) EB3 介导的 MT 动力学控制对于维持肺微血管基础通透性至关重要以及炎症介质引起的通透性增加。这些研究将解决以下问题具体目标： (1) VE-钙粘蛋白介导的信号传导在 EB3 磷酸化和抑制 MT 生长，从而发挥“由外向内”信号传导在建立基础细胞中的作用肺内皮细胞的通透性； (2) EB3 在调节 Ca2+ 信号传导中的关键作用，从而介导内皮通透性增加和肺水肿的发展。我们的期望是通过了解 VE-钙粘蛋白粘附如何发出 EB3 磷酸化信号以及 EB3 如何由此引发屏障通透性的增加将为肺液失调机制提供新的见解体内平衡。我们将利用最先进的技术，包括活细胞成像、突变体表达构建、基因转移和肺部炎症小鼠模型以实现特定目标。