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）：我们的建议是基于新的和重要的发现，涉及缺血后脑动脉中线粒体结构和功能的变化，这些发现具有科学意义，因为它们推翻了关于缺血后线粒体状态和功能的公认思想。这些发现具有转化的意义，因为它们开辟了新的治疗途径，可用于中风后的患者。从我们的发现中得出的总体假设是，缺血后线粒体（主要是内皮细胞）中自然发生的和药物诱导的变化导致脑血管功能改善，血脑屏障得到保护，神经损伤减少。我们发现线粒体在缺血损伤后比以前认为的更易变性 因此代表了中风患者的新疗法。我们使用的中风模型诱导的脑血管和脑损伤模式类似于在中风发作后3小时或更长时间才去除血管闭塞的患者中观察到的模式。几项研究表明，在卒中发作后3至4.5小时的时间窗内给予tPA显示出适度的治疗益处，超过4.5小时几乎没有益处。这些发病后3-4.5小时的患者代表了一个庞大且极其脆弱的人群。我们预计，除血栓清除外，线粒体靶向治疗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、离体脑动脉和体内脑循环中检验我们的假设。目标1.缺血性应激后脑血管线粒体“自然”发生形态和功能变化的测定。我们将测试的假设，线粒体的结构变化，包括大小，数量，和/或蛋白质含量，特别是在内皮细胞，与功能的变化，涉及维持扩张和缺血后的保护性反应。目标2.缺血性应激后脑血管线粒体动力学“可诱导”变化的测定。我们将测试的假设，药理学诱导的后处理将进一步改善脑缺血后的脑循环中的自然神经依赖性过程。