Arterial Smooth Muscle Chloride Channels

动脉平滑肌氯离子通道

• 批准号: 8195349
• 负责人: Jonathan H Jaggar
• 金额: $ 37万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8195349
• 关键词: Angiotensin II; Anions; Antibodies; Arteries; Arteriogram; Attenuated; Blood flow; Brain; Calcium; Caliber; Cations; Cell membrane; Cerebrovascular Circulation; Cerebrum; Chloride Channels; Chloride Ion; Chlorides; Cloning; Data; Dementia; Disease; Electrophysiology (science); Endothelium; Feedback; Fluorescence Resonance Energy Transfer; Hypertension; Image; Inbred SHR Rats; Intracellular Membranes; Investigation; Ion Channel; Measures; Mediating; Membrane; Membrane Potentials; Molecular; Molecular Target; Muscle Cells; Myography; Pathway interactions; Physiological; Property; Protein Splicing; Proteins; RNA Interference; RNA Splicing; Rattus; Reaction; Recombinants; Regional Blood Flow; Regulation; Resistance; Risk; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Stimulus; Stretching; Stroke; Swelling; Techniques; Testing; Up-Regulation; Variant; Vascular Diseases; Vasodilation; cerebral artery; cerebrovascular; constriction; inhibitor/antagonist; knock-down; mind control; normotensive; novel; patch clamp; pressure; response; stem; vasoconstriction; voltage

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. PUBLIC HEALTH RELEVANCE: Arterial smooth muscle cell ion channels modulate regional blood flow in the brain, but the molecular identity of anion channels, particularly chloride channels, in smooth muscle cells is poorly understood. Pathological alterations in cerebral artery smooth muscle cell ion channels are associated with vascular diseases, including stroke and dementia, but whether chloride channels are involved is unclear. Our proposal will investigate the novel hypothesis that recently discovered TMEM16A chloride channels are expressed in cerebral artery smooth muscle cells where they regulate physiological arterial contraction, and pathological alterations in these channels elevates cerebral artery contractility in hypertension.

描述（由申请人提供）：脑循环受到精细调节，但涉及的机制仍需要大量研究。脑动脉是控制脑局部血流的主要阻力血管。脑动脉平滑肌细胞膜电位控制细胞内钙（[Ca 2 +]i）浓度，并且是收缩性的主要调节剂。虽然已经鉴定了几种调节动脉平滑肌细胞膜电位的阳离子通道，但对阴离子通道的血管调节知之甚少。特别是，动脉平滑肌细胞氯（Cl-）通道的分子身份和生理功能尚不清楚。高血压与破坏性脑疾病的风险增加有关，包括中风和痴呆。高血压受试者的脑动脉去极化，导致收缩力升高，但尚不清楚Cl-通道在这种病理变化中的参与。本申请源自新的初步数据，表明最近发现的跨膜16 A Cl-（TMEM 16 A）通道在脑动脉平滑肌细胞中表达，并调节动脉收缩性。我们还提供了新的数据表明，高血压与TMEM 16 A通道的改变，提高脑动脉收缩性。将研究三个具体目标以检验中心假设，即脑动脉平滑肌细胞TMEM 16 A通道控制生理动脉收缩性，TMEM 16 A通道调节的改变提高高血压的收缩性。目的1将研究动脉平滑肌细胞中表达的TMEM 16通道的分子特性和调控。目的2阐明平滑肌细胞TMEM 16 A通道在调节动脉膜电位、[Ca ~（2+）]i和收缩性中的功能意义。目的3将探讨系统性高血压与平滑肌细胞TMEM 16 A通道的改变有关的假设，以及高血压中抑制肌细胞TMEM 16 A通道诱导血管舒张的假设。这一建议将提供重要的新信息，脑动脉调节平滑肌细胞氯离子通道，并将评估的潜力，TMEM 16 A通道是一个新的分子靶点调节收缩。 公共卫生相关性：动脉平滑肌细胞离子通道调节脑中的局部血流量，但平滑肌细胞中阴离子通道，特别是氯离子通道的分子特性知之甚少。脑动脉平滑肌细胞离子通道的病理改变与血管疾病有关，包括中风和痴呆，但氯离子通道是否参与尚不清楚。我们的提案将调查新的假设，最近发现的TMEM 16 A氯离子通道在脑动脉平滑肌细胞中表达，在那里它们调节生理动脉收缩，并且这些通道的病理改变提高了高血压患者的脑动脉收缩力。