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Investigating the fundamental mechanisms underlying the phenotypic diversity observed in RYR1-associated Malignant Hyperthermia.

研究 RYR1 相关恶性高热中观察到的表型多样性的基本机制。

基本信息

批准号：
MR/N002407/1
负责人：
金额：
$ 26.03万
依托单位：
University of Leeds
依托单位国家：
英国
项目类别：
Fellowship
财政年份：
2016
资助国家：
英国
起止时间：
2016 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FN002407%2F1
关键词：
Investigating fundamental mechanisms underlying phenotypic

项目摘要

Calcium is a crucial regulator of normal function within all cells but in skeletal muscle it has additional roles in allowing the muscle to contract. Therefore, muscle cells (myocytes) have evolved unique structures and pathways to regulate calcium levels within them. The normal functioning of these systems are incompletely understood, as is the detail of how they fail in disease. One of the most dramatic examples of skeletal muscle calcium dysregulation is a potentially lethal reaction to general anaesthetics (GA) called malignant hyperthermia (MH). People with a genetic risk for MH are apparently healthy until exposed to the strong anaesthetic gases which then results in a rapidly progressive and life-threatening (malignant) increase in heat generation (hyperthermia). The MH reaction is due to muscle over-activity from calcium dysregulation. These genetic changes in MH can lead to ongoing calcium dysregulation even without anaesthetic exposure. This then causes long-term adaptations within the myocytes, resulting in muscle pain and damage especially when exposed to stress such as exercise and statin medication. Exercise can also lead to excess heat production and the development of heat illness of which the most severe form known as heat stroke can be fatal. As a result, research into MH has benefits for various people; it can directly help patients at risk of MH (up to 1 in 2,000 people), but also patients with these other disease processes. The studies on MH have provided important discoveries on the mechanisms of normal skeletal muscle function, as well as revealed how such calcium dysregulation can cause problems in other tissues including the heart and brain. A problem with previous research has been the lack of availability of the correct samples to allow a suitable understanding of the mechanisms in humans. I am fortunate to be able to undertake this research in the only MH unit in the UK which has human tissue samples donated by patients undergoing investigations for MH.Recent studies have shown that calcium levels in skeletal myocytes are higher in people who have had MH compared to those who have not. Consequently, this research will address the fundamental need to understand how the genetic differences seen in patients with MH affect the entry and regulation systems of calcium in skeletal myocytes. To understand these mechanisms I will examine how calcium entry into myocytes from patients with MH differs to those without. The initial focus will be to study the most common and serious mutations using various molecular research techniques. One of the techniques I will use is highly specialised, but allows me to directly measure the amount of calcium in myocytes. To learn and import this technique to the UK, I will travel to America for six months. Once I have measured the calcium levels in the different myocyte samples, I can then use several cutting-edge research tools to try and identify the mechanisms of calcium dysregulation and how this can be controlled. After completing these sets of experiments, my research will then examine how the number of mutations affects the amount of calcium that enters and stays in cells. The reason for this is that there are some families with MH where the condition appears to result from the effects of more than one gene interacting with each other. This provides an additional genetic mechanism placing patients at risk of MH. The knowledge gained will allow doctors to better recognize how the genetic changes in patients at risk of MH are likely to affect the patient on exposure to GA, as a result allow patients to receive a safer GA.To summarise, by identifying the structures involved in short and long-term skeletal muscle calcium dysregulation and how they interact, this innovative research could detect potential targets for the development of new drugs. These could be used to prevent and treat MH and various long-term conditions associated with calcium dysregulation.

钙是所有细胞内正常功能的重要调节剂，但在骨骼肌中，它在使肌肉收缩方面具有额外的作用。因此，肌肉细胞（肌细胞）已经进化出独特的结构和途径来调节它们内部的钙水平。这些系统的正常功能尚未完全了解，它们在疾病中如何失效的细节也是如此。骨骼肌钙调节异常的一个最引人注目的例子是对全身麻醉剂（GA）的潜在致命反应，称为恶性高热（MH）。具有MH遗传风险的人显然是健康的，直到暴露于强烈的麻醉气体，然后导致快速进行性和危及生命的（恶性）发热（高热）增加。MH反应是由于钙调节异常引起的肌肉过度活动。MH中的这些遗传变化可导致持续的钙调节异常，即使没有麻醉暴露。这会导致肌细胞内的长期适应，导致肌肉疼痛和损伤，特别是当暴露于运动和他汀类药物等压力时。运动也会导致过多的热量产生和中暑的发展，其中最严重的形式被称为中暑可能是致命的。因此，对MH的研究对各种人都有好处;它可以直接帮助有MH风险的患者（高达2,000人中的1人），也可以帮助患有其他疾病的患者。对MH的研究为正常骨骼肌功能的机制提供了重要发现，并揭示了这种钙调节异常如何导致其他组织（包括心脏和大脑）出现问题。以前研究的一个问题是缺乏正确的样本，无法适当了解人类的机制。我很幸运能够在英国唯一的MH单位进行这项研究，该单位有接受MH调查的患者捐赠的人体组织样本。最近的研究表明，患有MH的人骨骼肌细胞中的钙水平高于那些没有的人。因此，这项研究将解决的基本需要，以了解遗传差异，在MH患者中看到的影响骨骼肌细胞钙的进入和调节系统。为了了解这些机制，我将研究如何钙进入心肌细胞从MH患者不同，那些没有。最初的重点将是使用各种分子研究技术研究最常见和最严重的突变。我将使用的技术之一是高度专业化的，但允许我直接测量肌细胞中的钙含量。为了学习并将这项技术引进英国，我将去美国旅行六个月。一旦我测量了不同肌细胞样本中的钙水平，我就可以使用几种尖端的研究工具来尝试和确定钙失调的机制以及如何控制这种机制。在完成这些实验后，我的研究将研究突变的数量如何影响进入和停留在细胞中的钙的数量。其原因是，有一些家庭与MH的条件似乎是由于一个以上的基因相互作用的影响。这提供了将患者置于MH风险中的额外遗传机制。所获得的知识将使医生能够更好地认识到MH风险患者的遗传变化如何可能影响患者暴露于GA，从而使患者接受更安全的GA。总之，通过确定参与短期和长期骨骼肌钙调节异常的结构以及它们如何相互作用，这项创新研究可以检测新药开发的潜在靶点。这些可用于预防和治疗MH和与钙调节异常相关的各种长期疾病。