Endothelial Preconditioning and Ischemic Brain Injury

内皮预处理和缺血性脑损伤

• 批准号: 6749438
• 负责人: Richard F Keep
• 金额: $ 29.02万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-25 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6749438
• 关键词: antioxidants; apoptosis; astrocytes; bioenergetics; blood brain barrier; blood glucose; bradykinin; brain circulation; brain injury; cardiovascular pharmacology; cellular pathology; cerebral ischemia /hypoxia; cytoprotection; immunocytochemistry; infarct; ischemic preconditioning; laboratory rat; mixed tissue /cell culture; morphology; neuropeptide receptor; pathologic process; purinergic receptor; reperfusion; stroke; terminal nick end labeling; tissue /cell culture; vascular endothelium; western blottings

DESCRIPTION (provided by applicant): Ischemic preconditioning (IPC) has proved to be one of the most effective methods of reducing ischemic brain damage in animal models of stroke. Attention has focused on the mechanisms by which neurons may be protected by such preconditioning. However, we have found that IPC also protects the endothelium, which forms the blood-brain barrier, from ischemic damage. 'Ischemic' preconditioning also protects cerebral endothelial cells in vitro from oxygen glucose deprivation induced injury indicating that there can be direct preconditioning of the endothelium. Damage to the cerebral endothelium may potentiate ischemic brain injury in a number of ways and determining mechanisms to reduce endothelial damage is particularly pertinent at the moment considering the role of endothelial injury (hemorrhagic transformation) in limiting the use of tissue plasminogen activator for the treatment of ischemic stroke. We will examine the mechanisms involved in cerebral endothelial preconditioning both in vivo (rat middle cerebral artery occlusion) and in vitro (primary cultures of rat cerebral microvessel endothelial cells). The in vitro experiments will facilitate exploration of the mechanisms involved in preconditioning while assuring that the preconditioning acts directly on the endothelium. The in vivo experiments will ensure that the mechanisms elucidated in vitro also occur in the whole animal as well as allowing an assessment of the effects of preconditioning on other parameters (such as blood flow, capillary morphology and infarction). Overall the proposal has three main goals. 1) Determine the time course of preconditioning and the extent of its effects on the endothelium (Specific Aim 1). 2) Determine the events that can trigger endothelial preconditioning (Specific Aim 2). 3) Determine what mechanisms are triggered to protect the endothelium (Specific Aim 3). These experiments should provide information on: A) Endogenous defense mechanisms that protect the cerebral endothelium from ischemic injury and which may be therapeutic targets. B) The role of endothelial preconditioning in the effects of IPC on the brain. C) The role of endothelial injury in the overall effects of ischemia on the brain.

描述（由申请人提供）：缺血预处理（IPC）已被证明是减少中风动物模型中缺血性脑损伤的最有效方法之一。 人们的注意力集中在神经元受到这种预处理保护的机制上。 然而，我们发现 IPC 还可以保护形成血脑屏障的内皮细胞免受缺血性损伤。 “缺血”预处理还可以在体外保护脑内皮细胞免受缺氧葡萄糖诱导的损伤，这表明可以对内皮进行直接预处理。 脑内皮损伤可能以多种方式加剧缺血性脑损伤，考虑到内皮损伤（出血性转化）在限制使用组织纤溶酶原激活剂治疗缺血性脑病中的作用，目前确定减少内皮损伤的机制尤其重要。缺血性中风。 我们将研究体内（大鼠大脑中动脉闭塞）和体外（大鼠脑微血管内皮细胞的原代培养物）脑内皮预处理所涉及的机制。 体外实验将有助于探索预处理所涉及的机制，同时确保预处理直接作用于内皮。 体内实验将确保体外阐明的机制也适用于整个动物，并允许评估预处理对其他参数（如血流、毛细血管形态和梗塞）的影响。 总体而言，该提案具有三个主要目标。 1) 确定预处理的时间过程及其对内皮细胞的影响程度（具体目标 1）。 2) 确定可触发内皮预处理的事件（具体目标 2）。 3) 确定触发什么机制来保护内皮（具体目标 3）。 这些实验应提供以下信息：A）保护脑内皮免受缺血性损伤的内源性防御机制，并且可能是治疗靶标。 B) 内皮预处理在 IPC 对大脑的影响中的作用。 C) 内皮损伤在大脑缺血总体影响中的作用。