Neurovascular Adhesion Receptors and Barrier Integrity

神经血管粘附受体和屏障完整性

基本信息

批准号：
7341074
负责人：
Gregory J Del Zoppo
金额：
$ 34.08万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-12-16 至 2010-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7341074
关键词：
Address Adhesions Appearance Astrocytes Attention Basal lamina Binding Blood Blood - brain barrier anatomy Blood Vessels Brain Brain Diseases Brain Hypoxia-Ischemia Cell Adhesion Cells Cerebrum Data DegP protease Degenerative Disorder Development Disruption Dystroglycan Endothelial Cells Endothelium Failure Family Glucose Goals Hypoxia Integrins Interruption Ischemia Ischemic Stroke Lead Liquid substance Matrix Metalloproteinases Mediating Metalloproteases Middle Cerebral Artery Occlusion Neurons Numbers Oxygen Permeability Phenotype Plasma Cells Receptor Cell Research Research Personnel Role Stroke Testing Therapeutic Tight Junctions Tissues Work adhesion receptor artery occlusion base clinically relevant cohesion deprivation foot inhibitor/antagonist member middle cerebral artery novel receptor receptor expression relating to nervous system small molecule

项目摘要

Ischemic stroke produces rapid profound loss of microvascular integrity. Early following focal ischemia detectable disruption in the permeability barrier of cerebral microvessels, and rapid changes in the matrix composition of their basal lamina occur. The hypotheses to be tested by this Proposal state i) that the interaction of matrix receptors on microvessel endothelial cells and astrocytes with the matrix components of the basal lamina are a major determinant of the blood-brain barrier phenotype, ii) that focal ischemia by middle cerebral artery occlusion (MCA:O) disrupts receptor-matrix interactions, and iii) that interruptions of the receptor-matrix interaction results in loss of the blood brain barrier phenotype. The phenotype of the permeability barrier involves the inter-endothelial tight junctions. But, adhesion of endothelial cells and astrocytes to the intact basal lamina matrix is also likely to be important. The vascular matrix is generated by endothelial cells and astrocytes in concert during development, and is maintained by both endothelial cells and astrocytes through their matrix adhesion receptors. Adhesion receptors which could bind cerebral microvascular endothelial cells and astrocytes to the basal lamina matrix include specific integrins and the a- and (3-dystroglycans. Based upon previous work and preliminary data, we propose that both integrins and dystroglycans are central to the integrity of the blood-brain and matrix barriers. The goal of this Project is to demonstrate that the action of specific members of these two adhesion receptor families is required for the integrity of the microvessel barrier functions, and that focal ischemia, hypoxia, and specific inhibitors that disrupt these receptor - matrix interactions, produce barrier failure. The Specific Aims are to: 1) Demonstrate that cell adhesion via cell receptors (integrins and dystroglycans) determine endothelial cell-matrix-astrocyte and blood brain barrier integrity; 2) Demonstrate that MCA:O or hypoxia significantly alter integrin-matrix and dystroglycan-matrix interactions at the endothelial cell-astrocyte interface; and 3) Demonstrate that the disruption of the cell adhesion receptor-matrix interactions occur independent of metalloproteinase expression. These studies provide a novel plausible explanation for the disruption of both the cerebral endothelial cell barrier to small molecules and the microvascular integrity immediately following focal ischemia. The specific use of select integrins and dystroglycans by astrocyte end-feet, and of PHntegrins by endothelial cells suggests the novel premise that their early disruption by focal ischemia is responsible for loss of the blood- brain barrier. Understanding the mechanisms of their expression and disruption is likely to lead to new testable approaches to preserve or selectively alter barrier function and microvessel integrity in other neurovascular degenerative disorders.

缺血性中风会产生微血管完整性的迅速丧失。局部缺血之后早期脑微血管的渗透性屏障中可检测的破坏，并且基质快速变化出现其基底层的组成。该提议状态i）要检验的假设微血管内皮细胞和星形胶质细胞上基质受体与基质的相互作用基底层的成分是血脑屏障表型的主要决定因素，II）大脑中部动脉闭塞（MCA：O）的局灶性缺血破坏了受体 - 矩阵相互作用，以及iii）中断受体 - 矩阵相互作用会导致血液流失脑屏障表型。渗透率屏障的表型涉及内层紧密连接。但是，内皮细胞和星形胶质细胞的粘附在完整的基底层基质上也可能很可能重要。血管基质是由内皮细胞和星形胶质细胞共同产生的开发，并通过其基质粘附来维持内皮细胞和星形胶质细胞受体。可以结合脑微血管内皮细胞和星形胶质细胞的粘附受体与基底层矩阵包括特定的整联蛋白和A-和（3-Dystroglycans。和初步数据，我们建议整联蛋白和多糖蛋白都是完整性的核心血脑和基质屏障。该项目的目的是证明特定的作用这两个粘附受体家族的成员需要微血管屏障的完整性功能，以及破坏这些受体基质的局灶性缺血，缺氧和特定抑制剂相互作用，产生障碍。具体目的是：1）证明细胞通过细胞粘附受体（整联蛋白和多个糖）确定内皮细胞 - 矩阵 - 胃细胞和血脑屏障正直; 2）证明MCA：O或缺氧会显着改变整联蛋白 - 马trix和Dystroglycan-matrix 内皮细胞 - 膜细胞界面的相互作用； 3）证明细胞的破坏粘附受体 - 基质相互作用发生独立于金属蛋白酶表达。这些研究为破坏两个脑内皮细胞的破坏提供了一种新颖的合理解释局灶性缺血之后，小分子和微血管完整性的障碍。具体通过星形胶质细胞末端使用精选的整合素和多根糖，以及内皮细胞的phntegrins 提出新的前提，即局灶性缺血的早期破坏是造成血液流失的原因脑屏障。了解其表达和破坏的机制可能导致新可测试的方法来保存或选择性地改变其他障碍功能和微血管完整性神经血管退化性疾病。