Arterial Smooth Muscle Chloride Channels

动脉平滑肌氯离子通道

基本信息

批准号：
8298982
负责人：
Jonathan H Jaggar
金额：
$ 42.03万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
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/8298982
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

项目摘要

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.

描述（由申请人提供）：脑循环受到精心调节，但涉及的机制仍需要进行大量研究。脑动脉是控制大脑区域血流至关重要的主要抗性血管。脑动脉平滑肌细胞膜电势控制细胞内钙（[CA2+] I）浓度，是收缩力的主要调节剂。尽管已经确定了调节动脉平滑肌细胞膜电位的几种阳离子通道，但对阴离子通道的血管调节却鲜为人知。特别是，动脉平滑肌细胞氯化物（CL-）通道的分子认同和生理功能尚不清楚。高血压与包括中风和痴呆在内的毁灭性脑疾病的风险增加有关。高血压受试者的脑动脉被去极化，导致收缩力升高，但cl-通道参与这种病理改变。该应用来自新的初步数据，表明最近发现的跨膜16a Cl-（TMEM16A）通道在脑动脉平滑肌细胞中表达并调节动脉收缩力。我们还提供了新的数据，表明高血压与提高脑动脉收缩力的TMEM16A通道的变化有关。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TM16A通道控制生理动脉收缩性和TMEM16A通道调节的改变可提高高血压的收缩性。 AIM 1将检查在动脉平滑肌细胞中表达的TMEM16通道的分子身份和调节。 AIM 2将阐明平滑肌细胞TMEM16A通道在控制动脉膜电位时的功能意义，[Ca2+] I和收缩力。 AIM 3将探讨以下假设：全身性高血压与平滑肌细胞TMEM16A通道的改变有关，并且在高血压中抑制肌细胞TMEM16A通道会诱导血管舒张。该提案将提供有关平滑肌细胞Cl-通道调节脑动脉调节的重要新信息，并评估TMEM16A通道是调节收缩力的新分子靶标的潜力。