Role of TRP channels and calcium signaling in cerebral arteries.

描述（由申请人提供）：心血管疾病（CVD），如高血压、中风和冠状动脉疾病，目前折磨着数百万美国人，每年花费超过4000亿美元。高血压的发病机制尚不清楚，目前的治疗侧重于降低血压或与其相关的后遗症，而不是导致疾病的因素。瞬态受体电位（Transient Receptor Potential， TRP）通道最近被证明在脉管系统中具有重要作用，为开发新的治疗模式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。最近的报道已经确定了TRPC3在激动剂依赖性血管收缩途径中。此外，TRPC6已被认为在压力诱导的血管收缩途径中发挥作用。综上所述，这些发现表明TRPM4作为TRPC3和TRPC6的下游介质。利用电生理学、钙成像和分离血管工作与RNAi技术相结合，目前的提案将测试以下三个假设；TRPC3和TRPC6的活性诱导细胞内钙的释放，钙的释放诱导TRPM4的活性，最终，该机制通过激动剂和压力介导的途径调节血管收缩。所提出的研究将显著增强我们对该通道在脉管系统中的调节作用的理解，并进一步加深我们对其他TRP通道在调节平滑肌兴奋性中的作用的认识。相关性：新的高血压预防治疗的发展依赖于我们对控制血压的基本内在机制的理解。该研究将提供一种新的分子机制，并为开发新的治疗方法提供令人兴奋的潜在靶点。

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.