Neurovascular Adhesion Receptors and Barrier Integrity

神经血管粘附受体和屏障完整性

• 批准号: 8395634
• 负责人: Gregory J Del Zoppo
• 金额: $ 33.8万
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8395634
• 关键词: Acute; Address; Adhesions; Amyloid; Astrocytes; Basal lamina; Binding; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Edema; Brain Injuries; Cell Line; Cell-Matrix Junction; Cells; Cerebral Ischemia; Cerebrovascular Disorders; Cerebrum; Chronic; Clinical; Complex; Data; Development; Disease; Dystroglycan; Edema; Endothelial Cells; Endothelium; Extravasation; Failure; Family member; Funding; Glucose; Goals; Hemorrhage; In Vitro; Infiltration; Injury; Integrin Binding; Integrins; Interruption; Ischemia; Ischemic Stroke; Lead; Liquid substance; Mediating; Modeling; Mus; Oxygen; Pathway interactions; Peptides; Permeability; Phenotype; Process; Proteins; Research; Risk; Signal Pathway; Signal Transduction; Stroke; Testing; Tight Junctions; Validation; Vascular Diseases; Work; adhesion receptor; base; clinically relevant; cohesion; deprivation; in vivo; inhibitor/antagonist; neurovascular unit; nonhuman primate; novel; prevent; protein expression; receptor; research study; response; scaffold; treatment strategy

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 occurs, with rapid loss of the endothelial cell ¿1 integrin-matrix receptors. In amyloid angiopathy, microvessel alterations increase the risk of microhemorrhages. The hypotheses to be tested by this competing renewal Proposal state that i) the interaction of matrix receptors on microvessel endothelial cells (and astrocytes) with matri components of the basal lamina are a major determinant of the blood-brain barrier phenotype, ii) focal cerebral ischemia disrupts receptor-matrix interactions, and iii) interruptions of receptor-matrix interactions result in loss of the blood brain barrier phenotype. We have shown that adhesion of endothelial cells to the intact basal lamina matrix is central to the integrity of the barrier. The barrier phenotype (e.g. tight junctions (TJs)) and vascular matrix are generated by endothelial cells and astrocytes in concert, and are maintained by both cell compartments. The expression of ¿1 integrins on endothelial cells and ¿¿-dystroglycan on astrocytes in vivo, and their responses to focal ischemia, are mimicked by primary endothelial cells and astrocytes of murine origin in culture. These responses are matrix-dependent. Based upon successful completed work and preliminary data, we propose that ¿1 integrins can determine TJ protein expression, and constitute the "vertical" component of the blood- brain and matrix barriers. The goal of this Project is to demonstrate that the actions of specific ¿1 integrin family members are required for the integrity of the microvessel barrier, and those specific integrin inhibitors, geneic constructs and knockdowns, focal ischemia, and A¿1 peptides disrupt the receptor-matrix interactions, producing barrier failure. The Specific Aims are to demonstrate that: 1) the interactions of ¿1 integrins on confluent endothelium with matrix proteins determine inter-endothelial cell cohesion by the TJ proteins, and these are modulated by astrocytes, 2) mechanisms of ¿1 integrin signaling within endothelial cells mediate the matrix adhesion receptor-mediated changes in TJ expression (without or with astrocytes), 3) experimental ischemia significantly alters endothelial cell TJ expression by altering the endothelial cell ¿1 integrin-matrix interactions, and 4) the exposure of endothelial cells (without or with astrocytes) to A¿-peptides modulates TJ expression and the microvessel permeability barrier phenotype via ¿1 integrin-dependent mechanisms. These novel studies provide a plausible explanation for the disruption of microvessel integrity immediately following focal ischemia and by amyloid angiopathy. The "vertical" component mediated by endothelial ¿1 integrin-matrix adhesion suggests the premise that its disruption is responsible for loss of the blood-brain barrier. Understanding the mechanisms of the ¿1 integrin-matrix adhesion is likely to lead to new testable approaches to preserve or selectively alter microvessel barrier function in other neurovascular disorders. PUBLIC HEALTH RELEVANCE: Ischemic stroke is a devastating disorder that disrupts important bonds between the cells lining the small blood vessels of the brain (microvessel endothelial cells), that are thought to prevent leakage of fluid from inside the vessels, causing blood leakage and brain swelling. We have recently found that molecules (¿1 integrins) that bind the endothelial cells to the scaffolding they sit on (matrix) within each microvessel are essential for maintaining the normal barrier to leakage, and that ischemic stroke quickly disrupts ¿1 integrins, thereby causing leakage to occur. This continuing research work will define the exact mechanisms by which endothelial cell ¿1 integrin-matrix binding maintains the barrier, and how its loss contributes to brain injury during ischemic stroke and other brain vascular disorders: fundamental studies needed for the development of new treatment strategies for stroke.

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，内皮细胞的迅速丢失»1整合素 - 矩阵 受体。在淀粉样蛋白血管病中，微血管的改变会增加微毛发的风险。通过这种竞争更新提出的建议，i）i）基本层层的基质内皮细胞（和星形胶质细胞）上基质内皮细胞（和星形胶质细胞）与基本层层的基质成分的相互作用是对血液屏障表型的主要决定性的主要确定，ii）焦点脑相互作用的受体互动，是II的主要决定性，相互作用导致血脑屏障表型的丧失。我们已经表明，内皮细胞对完整的基本层层基质的粘附对于屏障的完整性至关重要。屏障表型（例如紧密连接（TJ））和血管基质是由内皮细胞和星形胶质细胞共同产生的，并且由两个细胞室维持。在体内星形胶质细胞上对内皮细胞和dystroglycan的1个整联蛋白的表达，以及它们对局灶性缺血的反应，由原代内皮细胞和培养物中鼠起源的星形胶质细胞模仿。这些响应依赖于矩阵。基于成功完成的工作和初步数据，我们提出`1个整合蛋白可以确定TJ蛋白的表达，并构成血液和基质屏障的“垂直”成分。该项目的目的是证明特定的€1整联蛋白家族成员的作用是微血管屏障的完整性以及那些特定的整联蛋白抑制剂，基因构建体和敲除，局灶性缺血以及A e 1肽破坏接收器Matrix相互作用，从而产生障碍失败，从而产生障碍。具体目的是证明：1）„ 1整联蛋白在融合的邻苯乙烯与基质蛋白与基质蛋白的相互作用通过TJ蛋白确定的内皮细胞的凝聚力，这些相互作用是由星形胶质细胞调节的，2）在内皮细胞内的整合蛋白信号的机制调节，内皮细胞中的整合素信号传导，不带有Matrix粘合粘合物的粘合物介导的粘结式介导的粘结式介导（不适合）。实验性缺血通过改变内皮细胞»1整联蛋白 - 矩阵相互作用来显着改变内皮细胞TJ的表达，4）暴露于内皮细胞（没有或没有星形胶质细胞） 对于A肽，通过»1个整合素依赖性机制调节TJ表达​​和微血管渗透性屏障表型。这些新型研究为局灶性缺血和淀粉样血管病的破坏提供了一个合理的解释。内皮介导的“垂直”成分»1整合素 - 马trix广告表明，其破坏是造成血脑屏障的损失的前提。了解€1整联蛋白 - 矩阵粘合剂的机制可能会导致新的可测试方法来保存或选择性地改变其他神经血管疾病中的微血管屏障功能。 公共卫生相关性：缺血性中风是一种毁灭性疾病，它破坏了脑部小血管（微血管内皮细胞）之间的重要键，这些细胞被认为可以防止液体从血管内部泄漏，从而导致血液泄漏和脑肿胀。我们最近发现，将内皮细胞与它们坐在每个微血管内的脚手架（矩阵）上的分子（1个整合素）是必不可少的 为了保持正常的泄漏障碍，这种缺血性中风迅速破坏了1个整联蛋白，从而导致泄漏发生。这项持续的研究工作将定义内皮细胞的确切机制»1整联蛋白 - 马trix结合保持障碍，以及其损失如何在缺血性中风和其他脑血管疾病期间有助于脑损伤：开发新治疗策略所需的基本研究。