Neurovascular Adhesion Receptors and Barrier Integrity

神经血管粘附受体和屏障完整性

• 批准号: 7738486
• 负责人: Gregory J Del Zoppo
• 金额: $ 33.74万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-16 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7738486
• 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; 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; Oxygen; Permeability; Phenotype; Plasma Cells; Receptor Cell; Research; Research Personnel; Role; Stroke; Testing; Therapeutic; Tight Junctions; Tissues; Work; adhesion receptor; base; clinically relevant; cohesion; deprivation; foot; inhibitor/antagonist; member; novel; receptor; receptor expression; relating to nervous system; small molecule

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.

缺血性中风导致微血管完整性迅速严重丧失。局灶性缺血后早期 脑微血管通透性屏障可检测到的破坏以及基质的快速变化 其基底层的组成发生。本提案要检验的假设 i) 微血管内皮细胞和星形胶质细胞上的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) 大脑中动脉闭塞 (MCA:O) 引起的局灶性缺血会破坏受体基质 相互作用，以及 iii) 受体-基质相互作用的中断导致血液流失 脑屏障表型。通透性屏障的表型涉及内皮间紧密 路口。但是，内皮细胞和星形胶质细胞与完整基底层基质的粘附也可能 很重要。血管基质是由内皮细胞和星形胶质细胞协同产生的 发育，并由内皮细胞和星形胶质细胞通过其基质粘附来维持 受体。粘附受体可结合脑微血管内皮细胞和星形胶质细胞 基底层基质包括特定的整合素以及 a- 和 (3-dystroglycans)。基于之前的工作 和初步数据，我们认为整合素和肌营养不良聚糖对于细胞完整性至关重要。 血脑屏障和基质屏障。该项目的目标是证明具体的行动 这两个粘附受体家族的成员对于微血管屏障的完整性是必需的 功能，以及局灶性缺血、缺氧和破坏这些受体 - 基质的特定抑制剂 相互作用，产生屏障失效。具体目标是： 1) 证明细胞通过细胞粘附 受体（整合素和肌营养不良聚糖）决定内皮细胞-基质-星形胶质细胞和血脑屏障 正直; 2) 证明 MCA:O 或缺氧显着改变整合素基质和肌营养不良聚糖基质 内皮细胞-星形胶质细胞界面的相互作用； 3) 证明细胞的破坏 粘附受体-基质相互作用的发生与金属蛋白酶的表达无关。 这些研究为脑内皮细胞的破坏提供了新的合理解释。 局灶性缺血后立即形成小分子屏障和微血管完整性。具体的 星形胶质细胞末端足使用精选整合素和肌营养不良聚糖，内皮细胞使用 PHntegrin 提出了一个新的前提，即局部缺血导致的早期破坏是导致血液流失的原因。 脑屏障。了解它们的表达和破坏机制可能会带来新的结果 在其他疾病中保留或选择性改变屏障功能和微血管完整性的可测试方法 神经血管退行性疾病。