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

STIM1 介导的血管平滑肌 PLC 活性和 TRPC1 通道激活

基本信息

批准号：
BB/M018350/1
负责人：
Anthony Albert
金额：
$ 46.61万
依托单位：
St George's, University of London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2015
资助国家：
英国
起止时间：
2015 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FM018350%2F1
关键词：
STIM1 mediated PLC activity TRPC1

项目摘要

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.

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，造成英国四分之一的死亡。CVD每年花费英国超过290亿英镑的医疗保健费用加上工作日的损失。由于本港人口中的长者数目持续增加，这些由心血管疾病数字引致的数字将会增加。很明显，我们需要新的药物来治疗心血管疾病。我们血管的开放空间或“管腔”直径的减小会产生高血压，并减少流向我们器官的血液-这两个问题都会增加我们患心血管疾病的风险。众所周知，当血管壁中的肌肉细胞收缩过多时，它们会减小管腔直径。我们的研究重点是了解是什么原因导致这些肌肉细胞收缩过多。通过了解这些肌肉细胞以及它们如何控制血管的管腔直径，我们将有助于开发治疗CVD的新药。这些肌肉细胞内的钙含量与这些肌肉细胞的收缩高度相关，因此与血管的管腔直径密切相关。当钙水平增加太多时，它会导致肌肉细胞过度收缩并减少血管腔。我们研究的蛋白质，称为TRPC 1，形成专门的孔称为通道，发现在膜包围肌肉细胞。当这些TRPC 1通道被打开时，它们允许钙被转运到肌肉细胞中。如果我们能找到一种方法来减少TRPC 1通道的开放，我们就可以减少进入肌肉细胞的钙的量，这将减少这些细胞的收缩，并防止血管的直径变得太小：这将是治疗CVD的一个很好的策略。在这个提议中，我们计划利用小鼠的血管来研究是什么导致TRPC 1通道打开并让钙进入肌肉细胞，这是一个很好的动物物种，让我们了解发生在人类血管。我们的研究将大大推进我们的知识TRPC 1通道和如何控制血管的管腔直径。这将直接有助于开发新的CVD治疗方法。TRPC 1通道还控制来自身体其他部位的细胞中的钙水平，例如大脑，肾脏和肺。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。