Role of TRP channels and calcium signaling in cerebral arteries.

TRP 通道和钙信号在脑动脉中的作用。

基本信息

批准号：
7677356
负责人：
Albert Louis Gonzales
金额：
$ 2.9万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-15 至 2013-08-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7677356
关键词：
1,2-diacylglycerol Agonist American Arteries Blood Pressure Blood Vessels Blood flow Calcium Calcium Channel Calcium Signaling Caliber Calmodulin Cardiovascular Diseases Cations Cell membrane Cerebrum Chemicals Coronary Arteriosclerosis Data Development Diglycerides Disease Electrophysiology (science)Endothelium Event Goals Hypertension Image Inositol Investigation Ion Channel Knowledge Lead Measurement Mediating Mediator of activation protein Membrane Menthol Molecular Muscle Muscle Cells Neurons Osmolar Concentration Pathogenesis Pathway interactions Play Potassium Process RNA Interference Regulation Reporting Resistance Role Sarcoplasmic Reticulum Signal Pathway Signal Transduction Small Interfering RNA Smooth Muscle Smooth Muscle Myocytes Sodium Speed Stimulus Stretching Stroke Synapses Technology Temperature Testing Tissues Vascular Smooth Muscle Vasoconstrictor Agents Work blood pressure regulation cerebral artery constriction cost extracellular hypertension treatment inhibitor/antagonist member nerve supply novel pressure receptor research study response vasoconstriction voltage

项目摘要

DESCRIPTION (provided by applicant): Cardiovascular diseases (CVD), such as hypertension, stroke, and coronary artery disease currently afflict millions of Americans and at an annual cost greater than $400 billion dollars. The mechanisms responsible for the pathogenesis of hypertension are not well understood and current treatments focus on the reduction of blood pressure, or the sequelae associated with it, rather than the contributing factors that lead to the disease. Transient Receptor Potential (TRP) channels, which have recently been shown to have an important role in the vasculature, present an exciting target for the development of novel treatment paradigms. Our recent findings demonstrate that TRPM4 mediates smooth muscle cell depolarization and vasoconstriction in response to both intraluminal pressure and receptor-dependent agonists. Recent reports have identified TRPC3 in agonist dependent vasoconstriction pathways. In addition, TRPC6 has been suggested to play a role in pressure-induced vasoconstriction pathways. All together, these findings suggest that TRPM4 acts as a downstream mediator of TRPC3 and TRPC6. Using electrophysiology, calcium imaging, and isolated vessel work in combination with RNAi technology, the current proposal will test the following three hypotheses; that TRPC3 and TRPC6 activity elicits calcium release from intracellular stores, that the calcium release from stores induces TRPM4 activity, and ultimately, that the proposed mechanism modulate vasoconstriction through agonist- and pressure-mediated pathways. The proposed studies will significantly enhance our understanding of the channel's regulation in the vasculature and further our knowledge of the roles of other TRP channels in modulating smooth muscle excitability. Relevance: The development of new preemptive treatments for hypertension is dependent on our understanding of the basic intrinsic mechanisms that control blood pressure. The proposed study will provide a novel molecular mechanism, as well as exciting potential targets for the development of novel treatments.

描述（由申请人提供）：高血压、中风和冠状动脉疾病等心血管疾病 (CVD) 目前困扰着数百万美国人，每年造成的损失超过 4000 亿美元。高血压的发病机制尚不清楚，目前的治疗重点是降低血压或与之相关的后遗症，而不是导致疾病的促成因素。瞬时受体电位（TRP）通道最近被证明在脉管系统中具有重要作用，为新型治疗范例的开发提供了一个令人兴奋的目标。我们最近的研究结果表明，TRPM4 介导平滑肌细胞去极化和血管收缩，以响应腔内压力和受体依赖性激动剂。最近的报告已经在激动剂依赖性血管收缩途径中发现了 TRPC3。此外，TRPC6 已被认为在压力诱导的血管收缩途径中发挥作用。总而言之，这些发现表明 TRPM4 作为 TRPC3 和 TRPC6 的下游介质。目前的提案将利用电生理学、钙成像和离体血管工作与 RNAi 技术相结合来检验以下三个假设； TRPC3 和 TRPC6 活性引发细胞内钙储存释放，钙储存诱导 TRPM4 活性，最终，所提出的机制通过激动剂和压力介导的途径调节血管收缩。拟议的研究将显着增强我们对该通道在脉管系统中调节的理解，并进一步了解其他 TRP 通道在调节平滑肌兴奋性中的作用。相关性：新的高血压预防性治疗方法的开发取决于我们对控制血压的基本内在机制的理解。拟议的研究将为新疗法的开发提供新的分子机制以及令人兴奋的潜在目标。