Mitochondrial influences on cerebral arteries

描述（由申请人提供）：我们的提案是基于新的和重要的发现，涉及脑动脉缺血后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维。这些发现具有翻译意义，因为它们开辟了新的治疗途径，可用于中风患者。根据我们的发现，我们的总体假设是，线粒体（主要是缺血后的内皮细胞）的自然发生和药物诱导的变化，可以改善脑血管功能，保存血脑屏障，减少神经损伤。我们发现线粒体在缺血损伤后比以前认为的更有弹性

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.