Mitochondrial Influences on Cerebral Arteries

线粒体对脑动脉的影响

• 批准号: 8447025
• 负责人: DAVID W BUSIJA
• 金额: $ 35.46万
• 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 2014-11-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8447025
• 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.

描述（由申请人提供）：有限的研究表明，线粒体衍生因素在控制大脑循环中的重要作用超出了与能源供应有关的影响。因此，将线粒体去极化和/或增强ROS从线粒体中释放的因素激活了信号传导途径，导致大脑动脉的净扩张。此外，我们的初步数据表明，线粒体影响受胰岛素抵抗（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剂，但被IR损害。两个具体的目标将测试我们在大鼠中的假设和猜测：目标1。检查线粒体衍生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，激酶活化和线粒体ROS产生之间的关系。 b）阐明了由于线粒体去极化，激酶激活，ROS产生和浆膜钙激活的钾通道开口引起的扩张机制。 c）评估在介导综合扩张器反应中，在内皮和VSM细胞中产生的线粒体衍生因子的相互关系。 d）确定通过线粒体衍生的机制事先激活引起的预处理，改变了随后对线粒体衍生产物的脑血管反应。 e）探索生理刺激与线粒体激活之间的关系。 AIM 2。研究IR对线粒体衍生影响脑动脉的影响的研究。我们将：a）检查IR是否会减弱脑动脉的扩张剂反应，依赖于线粒体衍生的信号传导途径。 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）检查他汀类药物对动物的治疗是否恢复了IR中对线粒体衍生刺激的正常反应能力。我们预计我们的结果将导致改善患有脑血管疾病的患者的治疗。