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Mitochondrial influences on cerebral arteries

线粒体对脑动脉的影响

基本信息

批准号：
9197668
负责人：
DAVID W BUSIJA
金额：
$ 37.63万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2018-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9197668
关键词：
ATP sensitive potassium channel complex Blood - brain barrier anatomy Blood Vessels Brain Brain Edema Cells Cerebrovascular Circulation Cerebrovascular Trauma Cerebrovascular system Coagulation Process Cultured Cells Data Dilator Endothelium Excision Glucose Hour Infarction Injury Inner mitochondrial membrane Ischemia Lead Middle Cerebral Artery Occlusion Mitochondria Modeling Morbidity - disease rate Morphology Nervous System Trauma Neurons Oxygen Patient-Focused Outcomes Patients Pattern Pharmaceutical Preparations Pharmacology Process Proteins Resolution Role Stress Stroke Structure Systemic Therapy Testing Therapeutic Thinking Time Vascular Endothelium Vascular Smooth Muscle Vulnerable Populations base brain endothelial cell cell type cerebral artery cerebral hypoperfusion cerebrovascular clinically relevant conditioning deprivation improved improved outcome in vivo interest mitochondrial K(ATP) channel mortality neurovascular unit novel novel therapeutics preconditioning public health relevance response

项目摘要

DESCRIPTION (provided by applicant): Our proposal is based upon new and important findings involving changes in mitochondrial structure and function in cerebral arteries after ischemia which are of scientific interest because they overturn accepted thinking concerning mitochondrial status and function after ischemia. These findings are of translational interest because they open up novel therapeutic avenues which can be used in people following strokes. Our overall hypothesis, derived from our discoveries, is that naturally occurring and drug inducible changes in mitochondria, primarily in endothelium following ischemia, lead to improved cerebral vascular function, preserved blood-brain barrier, and reduced neurological injury. We find that mitochondria are more resiliant after ischemic insult than previously believed and thus represent a novel therapy in stroke patients. The stroke model we use induces patterns of cerebral vascular and brain injury similar to those seen in patients in which the vascular occlusion is not removed until 3 or more hours following the onset of stroke. Several studies have shown that tPA administration in a 3- to 4.5-hour window after stroke onset shows a modest therapeutic benefit with little benefit beyond 4.5 hours. These patients in the 3-4.5 hour post-onset period represent a large and extremely vulnerable population. We expect that mitochondrial targeting in addition to clot removal will lessen morbidity and mortality in these patients. We will test our hypothesis in cultured cerebral vascular endothelial cells, isolated cerebral arteries, and the in vivo cerebral circulation. Aim 1. Determination of "naturally" occurring morphological and functional changes in mitochondria in the cerebral vasculature following ischemic stress. We will test the hypothesis that structural changes in mitochondria, including size, numbers, and/or protein content, especially in endothelium, are correlated with functional changes involving maintained dilator and protective responses following ischemia. Aim 2. Determination of "inducible" changes in mitochondrial dynamics in the cerebral vasculature following ischemic stress. We will test the hypothesis that pharmacologically-induced post-conditioning will further improve upon natural mitochondrial-dependent processes in the cerebral circulation following ischemia.

描述（由申请人提供）：我们的提案基于涉及缺血后脑动脉线粒体结构和功能变化的新的重要发现，这些发现具有科学意义，因为它们推翻了有关缺血后线粒体状态和功能的公认观点。这些发现具有转化意义，因为它们开辟了可用于中风患者的新治疗途径。基于我们的发现，我们的总体假设是，线粒体（主要是缺血后的内皮细胞）自然发生的和药物诱导的变化可改善脑血管功能，保留血脑屏障，并减少神经损伤。我们发现线粒体在缺血性损伤后比以前认为的更有弹性因此代表了中风患者的一种新疗法。我们使用的中风模型诱发脑血管和脑损伤的模式，类似于在中风发作后 3 小时或更长时间才解除血管闭塞的患者中所见的情况。多项研究表明，在中风发作后 3 至 4.5 小时内服用 tPA 具有一定的治疗效果，但超过 4.5 小时后几乎没有效果。这些发病后 3-4.5 小时内的患者代表了一个庞大且极其脆弱的人群。我们预计，除了凝块去除之外，线粒体靶向将降低这些患者的发病率和死亡率。我们将在培养的脑血管内皮细胞、分离的脑动脉和体内脑循环中检验我们的假设。目的 1. 确定缺血应激后脑血管系统中线粒体“自然”发生的形态和功能变化。我们将检验这样的假设：线粒体的结构变化，包括大小、数量和/或蛋白质含量，尤其是内皮细胞的结构变化，与缺血后维持扩张和保护反应的功能变化相关。目标 2. 确定缺血应激后脑血管系统中线粒体动力学的“诱导”变化。我们将检验这样的假设：药物诱导的后处理将进一步改善缺血后脑循环中自然的线粒体依赖性过程。