Mitochondrial Influences on Cerebral Arteries

描述（由申请方提供）：有限的研究表明，脑源性因子在控制脑循环中的重要作用超出了与能量供应相关的影响。因此，使线粒体脱钙和/或增加ROS从线粒体释放的因子激活导致脑动脉净扩张的信号传导途径。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，脑源性影响是脑血管紧张度的关键调节因子，但受到IR的影响。两个具体目标将在大鼠中检验我们的假设和推测：目标1。脑源性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）阐明由于线粒体去极化、激酶活化、ROS产生和质膜钙激活钾通道开放引起的扩张机制。C）评估内皮细胞和VSM细胞中产生的血管源性因子在介导整体扩张反应中的相互关系。D）确定由脑源性机制的先前激活诱导的预处理是否改变随后对脑源性产物的脑血管反应。E）探索生理刺激与线粒体活化之间的关系。目标二。研究IR对脑动脉的脑源性影响。我们将：A）检查IR是否减弱依赖于脑动脉源性信号通路的脑动脉扩张反应。B）确定IR降低脑动脉对脑源性影响的反应性的机制。C）检查用他汀类药物治疗动物是否恢复了IR中对脑源性刺激的正常反应性。我们期望我们的结果将导致改善脑血管疾病患者的治疗。公共卫生相关性：慢性脑血管功能不全，发生在IR，导致神经系统疾病，如阿尔茨海默病和中风。然而，线粒体功能障碍的潜在作用尚未研究。目前的治疗方案并不是最佳的，我们希望我们的研究结果将导致新的和改进的治疗方法，以预防或减缓老年人神经系统疾病的发作。

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.