Mitochondrial influences on cerebral arteries

线粒体对脑动脉的影响

• 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
• 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

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）：我们的建议基于新的重要发现，涉及缺血后脑动脉中线粒体结构和功能的变化，这具有科学意义，因为它们推翻了缺血后的线粒体状态和功能的看法。这些发现具有转化的兴趣，因为它们开辟了新颖的治疗途径，这些途径可用于跟随中风的人。我们的总体假设是从我们的发现中得出的，是在缺血后的内皮中自然发生和药物诱导的变化，主要在内皮中，导致大脑血管功能改善，保留的血脑屏障，并减少神经系统损伤。我们发现，缺血性侮辱后的线粒体比以前认为的更具弹性 因此代表了中风患者的新疗法。我们使用的中风模型会诱导脑血管和脑损伤的模式，类似于在中风发作后3或更长时间才去除血管闭塞的患者中。几项研究表明，中风发作后3至4.5小时的TPA给药显示出适中的治疗益处，几乎没有4.5小时的益处。这些患者在发生后3-4.5小时内代表了大量且极其脆弱的人群。我们预计线粒体靶向除凝块清除外还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测试我们的假设。目的1。在缺血性压力后，确定线粒体中线粒体中的形态和功能变化的确定。我们将检验以下假设：线粒体的结构变化，包括大小，数量和/或蛋白质含量，尤其是在内皮中，与涉及局部缺血后延伸器和保护性反应的功能变化相关。目标2。确定缺血性压力后脑血管中线粒体动力学的“诱导”变化。我们将检验以下假设：缺血后，在缺血后，药理学引起的后条件将进一步改善天然线粒体依赖性过程。