Arterial Smooth Muscle Chloride Channels

描述(申请人提供)：大脑循环被精确地调节，但涉及的机制仍然需要大量的研究。脑动脉是控制脑局部血流的重要阻力血管。脑动脉平滑肌细胞膜电位控制细胞内钙离子浓度，是收缩功能的主要调节因子。虽然已经确定了几种调节动脉平滑肌细胞膜电位的阳离子通道，但对阴离子通道对血管的调节知之甚少。特别是，动脉平滑肌细胞氯离子通道的分子同一性和生理功能尚不清楚。高血压与包括中风和痴呆症在内的破坏性脑部疾病的风险增加有关。高血压患者的大脑动脉被去极化，导致收缩能力增强，但氯通道参与这种病理变化尚不清楚。这一应用源于新的初步数据，表明最近发现的跨膜16A1-(TMEM16A)通道在大脑动脉平滑肌细胞中表达，并调节动脉收缩。我们还提供了新的数据，表明高血压与TMEM16A通道的改变有关，TMEM16A通道提高了大脑动脉的收缩能力。为了验证大脑动脉平滑肌细胞TMEM16A通道控制生理性动脉收缩的中心假说，以及TMEM16A通道调节的改变提高高血压患者的收缩能力这一中心假说，我们将研究三个特定的目标。目的1研究动脉平滑肌细胞表达的TMEM16通道的分子特性和调控。目的2阐明平滑肌细胞TMEM16A通道在控制动脉膜电位、[Ca~(2+)]i和收缩功能中的功能意义。目的探讨全身性高血压与血管平滑肌细胞TMEM16A通道改变有关的假说，以及在高血压时抑制心肌细胞TMEM16A通道可诱导血管扩张的假说。这一建议将提供关于平滑肌细胞氯通道对大脑动脉调节的重要新信息，并将评估TMEM16A通道作为调节收缩性能的新分子靶点的潜力。

DESCRIPTION (provided by applicant): Cerebral circulation is exquisitely regulated, but mechanisms involved still require considerable investigation. Cerebral arteries are major resistance vessels critical for control of brain regional blood flow. Cerebral artery smooth muscle cell membrane potential controls intracellular calcium ([Ca2+]i) concentration and is a major regulator of contractility. Although several cation channels that regulate arterial smooth muscle cell membrane potential have been identified, vasoregulation by anion channels is poorly understood. In particular, the molecular identity and physiological functions of arterial smooth muscle cell chloride (Cl-) channels is unclear. Hypertension is associated with increased risk for devastating cerebral diseases, including stroke and dementia. Cerebral arteries from hypertensive subjects are depolarized, leading to elevated contractility, but involvement of Cl- channels in this pathological alteration is not known. This application derives from novel preliminary data suggesting that recently discovered transmembrane 16A Cl- (TMEM16A) channels are expressed in cerebral artery smooth muscle cells and regulate arterial contractility. We also provide novel data indicating that hypertension is associated with alterations in TMEM16A channels that elevate cerebral artery contractility. Three specific aims will be investigated to test the central hypothesis that cerebral artery smooth muscle cell TMEM16A channels control physiological arterial contractility and alterations in TMEM16A channel regulation elevate contractility in hypertension. Aim 1 will examine the molecular identity and regulation of TMEM16 channels expressed in arterial smooth muscle cells. Aim 2 will elucidate the functional significance of smooth muscle cell TMEM16A channels in controlling arterial membrane potential, [Ca2+]i and contractility. Aim 3 will explore the hypothesis that systemic hypertension is associated with an alteration in smooth muscle cell TMEM16A channels and that inhibiting myocyte TMEM16A channels in hypertension induces vasodilation. This proposal will provide significant novel information concerning cerebral artery regulation by smooth muscle cell Cl- channels and will evaluate the potential that TMEM16A channels are a new molecular target for modulating contractility.