STIM1-mediated PLC activity and TRPC1 channel activation in vascular smooth muscle

英国心脏基金会最近的一项调查显示，心血管疾病（CVD），如心绞痛、心脏病发作、心力衰竭和中风，导致了英国四分之一的死亡。心血管疾病每年还会给英国带来290亿英镑的医疗费用和工作日损失。这些由心血管疾病引起的数字将随着我国人口中老年人数量的持续增长而增加。很明显，我们需要新的药物来治疗心血管疾病。血管的开放空间或“腔”直径的减小会导致高血压，减少流向器官的血液——这两个问题都会增加我们患心血管疾病的风险。众所周知，当血管壁上的肌肉细胞收缩过度时，它们会减小管腔直径。我们的研究重点是了解是什么导致这些肌肉细胞过度收缩。通过更多地了解这些肌肉细胞以及它们如何控制血管管腔直径，我们将有助于开发治疗心血管疾病的新药。这些肌肉细胞内的钙含量与这些肌肉细胞的收缩密切相关，因此也与血管的管腔直径密切相关。当钙含量增加过多时，它会导致肌肉细胞过度收缩，减少血管腔。我们研究了一种叫做TRPC1的蛋白质，这种蛋白质在肌肉细胞周围的膜上形成称为通道的特殊孔。当这些TRPC1通道打开时，它们允许钙被运输到肌肉细胞中。如果我们能找到一种减少TRPC1通道打开的方法，我们就可以减少进入肌肉细胞的钙量，从而减少这些细胞的收缩，防止血管直径变得太小：这将是治疗心血管疾病的一个极好的策略。在这个提案中，我们计划利用老鼠的血管来研究是什么原因导致TRPC1通道打开并让钙进入肌肉细胞，老鼠是一个很好的动物物种，可以让我们了解人类血管中发生的事情。我们的研究将大大提高我们对TRPC1通道和如何控制血管管腔直径的认识。这将直接有助于开发新的心血管疾病治疗方法。TRPC1通道还控制着身体其他部位（如大脑、肾脏和肺部）细胞中的钙水平。因此，我们的研究也将有助于了解涉及各种其他身体系统的疾病。

A recent British Heart Foundation survey showed that cardiovascular diseases (CVD) such as angina, heart attack, heart failure, and stroke cause one quarter of all deaths in the UK. CVD also costs the UK over £29 billion a year in healthcare plus loss of work days. These figures caused by CVD numbers will increase as the number of elderly people in our population continues to grow. It is clear we need new drugs to treat CVD.A decrease in the diameter of the open space or 'lumen' of our blood vessels produces high blood pressure and reduces blood flowing to our organs - both these problems increase the risk of us developing CVD. It is known that when muscle cells found in the walls of blood vessels contract too much they decrease the lumen diameter. Our research focuses on understanding what causes these muscle cells to contract too much. By knowing more about these muscle cells and how they control lumen diameter of blood vessels we will help develop new drugs to treat CVD.The amount of calcium inside these muscle cells is highly associated with contraction of these muscle cells and therefore the lumen diameter of blood vessels. When calcium levels increase too much it causes the muscle cells to excessively contract and reduce the lumen of blood vessels. We investigate proteins, called TRPC1, which form specialised holes called channels that are found in the membrane that surrounds muscle cells. When these TRPC1 channels are opened they allow calcium to be transported into muscle cells. If we could find a way to reduce TRPC1 channels from opening, we could reduce the amount of calcium entering muscle cells, which would reduce contraction of these cells, and prevent the diameter of blood vessels from becoming too small: this would be an excellent strategy for treating CVD.In this proposal, we plan to investigate what causes TRPC1 channels to open and let calcium into muscle cells using the blood vessels of mice, which are an excellent animal species for allowing us to understand what happens in human blood vessels.Our research will greatly advance our knowledge on TRPC1 channels and on how the lumen diameter of blood vessels may be controlled. This will directly help in the development of new treatments for CVD. TRPC1 channels also control the level of calcium in cells from other parts of the body such as the brain, kidneys and lungs. Therefore our studies will also help understand diseases involving a variety of other body systems.