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：
7017932
负责人：
Gregory J Del Zoppo
金额：
$ 41.83万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
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

项目摘要

DESCRIPTION (provided by applicant): 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 (MCAO) 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 ¿ 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 MCAO 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 ¿1 integrins 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.

描述（由适用提供）：缺血性中风会产生微血管完整性的快速造成的快速丧失。在局灶性缺血之后，在脑部微血管的渗透性屏障中可检测到可检测到的破坏，并发生了基础层的基质组成的快速变化。该提议状态i）在微分离内皮细胞上的基质受体和星形胶质细胞与基础层层的基质成分的相互作用是血脑屏障表型的主要决定因素，II）是脑部脑部脑部脑部的主要决定因素（MC）。受体矩阵相互作用的中断导致血脑屏障表型的丧失。渗透率屏障的表型涉及内层间紧密连接。但是，内皮细胞和星形胶质细胞的粘合剂对完整的基本层层基质也很重要。发育过程中的内皮细胞和星形胶质细胞会产生血管基质，并通过其基质粘附受体通过内皮细胞和星形胶质细胞维持。可以结合脑微血管内皮细胞和星形胶质细胞与碱性层层基质的粘附受体包括特定的整合素和A和€dystroglycans。基于先前的工作和初步数据，我们建议整联蛋白和多糖糖都对血脑障碍和基质屏障的完整性都是核心。该项目的目的是证明这两个依从性受体家族的特定成员的作用是微血管屏障功能的完整性所必需的，并且局灶性缺血，缺氧和特定的抑制剂破坏了这些受体 - 基质相互作用，会产生障碍。具体目的是：1）证明细胞受体（整联蛋白和多糖糖）的细胞粘合剂确定内皮细胞 - 矩阵 - 骨细胞和血脑屏障的完整性； 2）证明MCAO或缺氧会在内皮细胞 - 核细胞界面上显着改变整联蛋白 - 马trix和Dystroglycan-matrix相互作用； 3）证明细胞粘附受体 - 矩阵相互作用的破坏独立于金属蛋白酶表达。这些研究为局灶性缺血后紧接的小分子的脑内皮细胞屏障和微血管完整性的破坏提供了一种新的合理解释。星形胶质细胞末端对精选整联蛋白和多糖糖的特定用途，以及内皮细胞的1个整联蛋白表明，新的前提是，局灶性缺血的早期破坏是导致血液脑屏障丧失的。了解其表达和破坏的机制可能会导致新的可测试方法，以保留或选择性地改变其他神经血管退行性疾病中的屏障功能和微血管完整性。