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Microvascular injury after Subarachnoid Hemorrhage

蛛网膜下腔出血后微血管损伤

基本信息

批准号：
7809523
负责人：
FATIMA A SEHBA
金额：
$ 29.37万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7809523
关键词：
Accounting Acute Acute Brain Injuries Affect Aneurysmal Subarachnoid Hemorrhages Angiography Animal Behavior Animals Apoptosis Aspirin Attention Basal Lamina Collagen Basal lamina Behavior Blood Blood - brain barrier anatomy Blood Platelets Blood Pressure Blood Vessels Blood flow Brain Brain Injuries Cause of Death Cerebral Ischemia Cerebrovascular Circulation Cerebrum Cessation of life Collagen Type IV Data Development Electron Microscopy Elements Endothelial Cells Endothelium Event Experimental Designs Experimental Models Extravasation Fibrin Foundations Gelatinase B Grooming Hemorrhage Horseradish Peroxidase Hour Human Image Immunofluorescence Immunologic Impairment Injection of therapeutic agent Injury Intracranial Aneurysm Intracranial Pressure Ischemia Laser-Doppler Flowmetry Matrix Metalloproteinases Measures Microtomy Microvascular Permeability Nature Nervous System Physiology Neurologic Examination Neurological outcome Neurological status Neurophysiology - biologic function Outcome Patients Perforation Perfusion Pharmaceutical Preparations Pharmacological Treatment Platelet Aggregation Inhibition Platelet aggregation Proteins Rattus Recovery Research Design Resolution Role Rupture Ruptured Aneurysm SB 3CT compound Saline Serum Proteins Signal Transduction Site Source Spasm Specimen Staining method Stains Stroke Structural Protein Structure Subarachnoid Hemorrhage Subarachnoid Space Testing Therapeutic Time Tracer Travel blood perfusion collagenase constriction design disability effective therapy feeding foot improved inhibitor/antagonist prevent rat endothelial barrier antigen research study therapy design therapy outcome time interval

项目摘要

DESCRIPTION (provided by applicant): Aneurysmal subarachnoid hemorrhage (SAH) accounts for 5-10% of annual stroke cases. 50% of the patients die within 30 days with most deaths occurring within the first 48 hours. Acute brain injury after SAH is ischemic in nature and develops within the first 48 hours with mechanisms that are poorly understood. No effective treatment for it currently exists. We have found structural injury in cerebral microvessels after SAH that could affect their function and contribute to acute ischemia. This study investigates the effect of structural injury on microvessel function and the role of intraluminal platelet aggregation in initiating these events after SAH. In an experimental model of SAH we have found intraluminal platelet aggregation, degradation of collagen IV, the major protein of basal lamina, and activation of vascular collagenases within hours after SAH. This study will test the hypotheses that platelet aggregation: 1. reduces microvascular perfusion and 2. initiates the destruction of perivascular collagen IV and thereby causes local breaches of the blood-brain barrier. SAH will be induced in the rat by endovascular perforation. Cerebral blood flow, blood pressure and intracranial pressure will be continuously recorded. Cerebral microvessels (slOOum) will be examined for perfusion, blood-brain barrier function, platelet aggregation, endothelial injury, matrix metalloproteinase-9 activation, and collagen IV loss during the first 48 hours after SAH. The effect of early pharmacological inhibition of platelet aggregation on microvascular perfusion and structural changes will be investigated. Animal behavior and neurological status will be examined to establish the outcome of this therapy on neural function. The experimental design will focus on four major questions: 1) what is the effect of intraluminal platelet aggregation on microvascular perfusion after SAH?, 2) do intraluminal platelet aggregates act as initiators of basal lamina degradation and blood brain barrier disruption after SAH?, 3) what fine structural changes occur in the microvasculature after SAH?, and 4) does early pharmacological inhibition of platelet aggregation improve neurological outcome? This study will extend our current understanding of early microvascular injury after SAH, and will evaluate the therapeutic potential of post-hemorrhage blockade of platelet aggregation.

描述（申请人提供）：动脉瘤性蛛网膜下腔出血（SAH）占每年卒中病例的5-10%。50%的患者在30天内死亡，大多数死亡发生在头48小时内。SAH后的急性脑损伤本质上是缺血性的，并在最初48小时内发展，其机制尚不清楚。目前尚无有效的治疗方法。我们发现SAH后脑微血管的结构损伤可能影响其功能并导致急性缺血。本研究探讨了结构损伤对微血管功能的影响，以及腔内血小板聚集在SAH后引发这些事件的作用。在SAH的实验模型中，我们发现SAH后数小时内腔内血小板聚集，基底膜主要蛋白IV胶原降解，血管胶原酶活化。本研究将检验血小板聚集的假设：1。2.减少微血管灌注。引发血管周围胶原蛋白IV的破坏，从而导致局部血脑屏障的破坏。大鼠血管内穿孔可诱发SAH。连续记录脑血流量、血压和颅内压。在SAH后的前48小时内，将检查脑微血管（slOOum）的灌注、血脑屏障功能、血小板聚集、内皮损伤、基质金属蛋白酶-9激活和胶原IV丢失。研究早期药物抑制血小板聚集对微血管灌注和结构改变的影响。将检查动物行为和神经系统状态，以确定该疗法对神经功能的影响。实验设计将重点关注四个主要问题：1)腔内血小板聚集对SAH后微血管灌注的影响是什么？2)腔内血小板聚集是否作为SAH后基底膜降解和血脑屏障破坏的启动物？3) SAH后微血管发生了哪些细微的结构变化？4)早期药物抑制血小板聚集是否能改善神经预后？本研究将扩展我们目前对SAH后早期微血管损伤的认识，并将评估出血后阻断血小板聚集的治疗潜力。