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。

• 批准号: 7910472
• 负责人: Albert Louis Gonzales
• 金额: $ 2.92万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 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/7910472
• 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

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）：心血管疾病（CVD），例如高血压，中风和冠状动脉疾病，目前遭受了数百万美国人的折磨，并且每年成本超过4000亿美元。负责高血压发病机理的机制尚不清楚，目前的治疗集中于血压的降低或与之相关的后遗症，而不是导致疾病的导致因素。瞬态受体电位（TRP）通道最近已被证明在脉管系统中具有重要作用，为开发新的治疗范式提供了一个令人兴奋的目标。我们最近的发现表明，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。最近的报告已经确定了激动剂依赖性血管收缩途径中的TRPC3。此外，已经建议TRPC6在压力诱导的血管收缩途径中发挥作用。这些发现一起表明TRPM4充当TRPC3和TRPC6的下游介体。使用电生理学，钙成像和孤立的血管与RNAi技术结合使用，当前的建议将检验以下三个假设。 TRPC3和TRPC6活性从细胞内存储中释放了钙，从商店中钙释放会诱导TRPM4活性，最终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脉管系统调节的理解，并进一步了解其他TRP通道在调节平滑肌肉兴奋性中的作用。相关性：开发新的高血压预先治疗方法取决于我们对控制血压的基本内在机制的理解。拟议的研究将提供一种新颖的分子机制，以及为开发新治疗的激动人心的潜在目标。