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，线粒体衍生因子在控制脑循环方面的重要作用超出了与能量供应相关的影响。因此，线粒体去极化和/或增加线粒体ROS释放的因素激活了导致脑动脉净扩张的信号通路。此外，我们的初步数据表明，线粒体的影响受到胰岛素抵抗（IR）的不利影响。我们的总体假设是，线粒体来源的影响是脑血管张力的关键调节因子，但受到IR的损害。两个特定目标将在大鼠身上验证我们的假设和推测：线粒体来源的影响在脑动脉介导反应中的作用的研究。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)阐明由线粒体去极化、激酶激活、ROS生成和质乳钙活化钾通道打开引起的扩张机制。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剂反应中的相互关系。D)确定预先激活线粒体来源机制所诱导的预处理是否会改变随后脑血管对线粒体来源产物的反应。E)探索生理刺激与线粒体激活之间的关系。目标2。IR对线粒体源性脑动脉影响的研究。我们将：A)研究IR是否减弱依赖线粒体来源信号通路的脑动脉扩张反应。B)确定IR降低脑动脉对线粒体来源影响的反应性的机制。C)检查他汀类药物治疗是否能恢复动物对IR中线粒体来源刺激的正常反应。我们期望我们的研究结果将有助于改善脑血管疾病患者的治疗。