Mitochondrial Influences on Cerebral Arteries

线粒体对脑动脉的影响

• 批准号: 8038326
• 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 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8038326
• 关键词: Affect; Alzheimer' s Disease; Animals; Antioxidants; Area; Attenuated; Blood Vessels; Brain; Calcium; Calcium-Activated Potassium Channel; Cells; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrum; Chronic; Data; Development; Dilator; Disease; Energy Supply; Generations; Health; Impairment; Insulin Resistance; Investigation; Lead; Link; Mediating; Mitochondria; Nature; Neurologic; Patients; Phosphotransferases; Physiological; Play; Potassium; Prevention; Production; Rattus; Reactive Oxygen Species; Relative (related person); Role; Signal Pathway; Smooth Muscle Myocytes; Stimulus; Stress; Stroke; Testing; Therapeutic; Treatment Protocols; Vascular Endothelium; Vascular Smooth Muscle; Vasodilation; aging population; cerebral artery; cerebrovascular; diabetic; improved; mitochondrial K(ATP) channel; mitochondrial dysfunction; nervous system disorder; neurovascular unit; preconditioning; prevent; response

DESCRIPTION (provided by applicant): Limited studies indicate an important role of mitochondrial-derived factors in the control of the cerebral circulation beyond effects which are related to energy supply. Thus, factors which depolarize mitochondria and/or augment the release of ROS from mitochondria activate signaling pathways leading to net dilation of cerebral arteries. Furthermore, our preliminary data indicate that mitochondrial influences are adversely affected by insulin resistance (IR). Our overall hypothesis is that mitochondrial-derived influences are key regulators of cerebral vascular tone but are compromised by IR. Two Specific Aims will test our hypotheses and speculations in rats: Aim 1. Examination of the roles of mitochondrial-derived influences in mediating responses of cerebral arteries. We will: A) Determine the relationship among cerebral arterial vasodilation, mitochondrial depolarization, kinase activation, and mitochondrial ROS production. B) Elucidate the mechanisms of dilation due to mitochondrial depolarization, kinase activation, ROS generation, and plasmalemmal calcium-activated potassium channel opening. C) Evaluate the inter-relationships of mitochondrial-derived factors produced in endothelium and VSM cells in mediating integrated dilator responses. D) Determine whether preconditioning, induced by prior activation of mitochondrial-derived mechanisms, alters subsequent cerebrovascular responses to mitochondrial-derived products. E) Explore the relationship between physiological stimuli and mitochondrial activation. Aim 2. Investigation of the effects of IR on mitochondrial-derived influences on cerebral arteries. We will: A) Examine whether IR attenuates dilator responses of cerebral arteries dependent upon mitochondria-derived signaling pathways. B) Determine the mechanisms by which IR reduces the responsiveness of cerebral arteries to mitochondrial-derived influences. C) Examine whether treatment of animals with statins restores normal responsiveness to mitochondrial-derived stimuli in IR. We expect that our results will lead to the improved treatment of patients suffering from cerebrovascular disease. PUBLIC HEALTH RELEVANCE: Chronic cerebral vascular insufficiency, which occurs in IR, leads to neurological diseases such as Alzheimer's disease and strokes. However, the potential role of mitochondrial dysfunction has not been studied. Current treatment regimens are not optimal and we expect that the results of our studies will lead to new and improved therapies to prevent or slow the onset of neurological diseases in an aging population.

描述（由申请人提供）：有限的研究表明线粒体衍生因子在控制脑循环中除了与能量供应相关的作用之外还具有重要作用。因此，使线粒体去极化和/或增加线粒体释放ROS的因子激活信号通路，导致脑动脉净扩张。此外，我们的初步数据表明线粒体影响受到胰岛素抵抗（IR）的不利影响。我们的总体假设是，线粒体衍生的影响是脑血管张力的关键调节因子，但会受到 IR 的影响。两个具体目标将在大鼠中测试我们的假设和推测： 目标 1. 检查线粒体衍生的影响在介导脑动脉反应中的作用。我们将： A) 确定脑动脉血管舒张、线粒体去极化、激酶激活和线粒体 ROS 产生之间的关系。 B) 阐明由于线粒体去极化、激酶激活、ROS 生成和质膜钙激活钾通道开放而导致的扩张机制。 C) 评估内皮细胞和 VSM 细胞中产生的线粒体衍生因子在介导综合扩张器反应中的相互关系。 D) 确定由线粒体衍生机制的先前激活诱导的预处理是否会改变随后的脑血管对线粒体衍生产物的反应。 E) 探索生理刺激与线粒体激活之间的关系。目标 2. 研究 IR 对线粒体衍生的脑动脉影响的影响。我们将： A) 检查 IR 是否会减弱依赖于线粒体衍生信号通路的脑动脉扩张器反应。 B) 确定 IR 降低脑动脉对线粒体衍生影响的反应性的机制。 C) 检查用他汀类药物治疗动物是否可以恢复 IR 中线粒体衍生刺激的正常反应性。我们期望我们的结果将改善脑血管疾病患者的治疗。公共健康相关性：IR 中发生的慢性脑血管功能不全会导致阿尔茨海默病和中风等神经系统疾病。然而，线粒体功能障碍的潜在作用尚未得到研究。目前的治疗方案并不是最佳的，我们期望我们的研究结果将带来新的和改进的疗法，以预防或减缓老龄化人口中神经系统疾病的发作。