Uncovering the Molecular Basis of Malignant Hyperthermia

描述(申请人提供)：这项多中心PPG的长期目标是确定由RyR1和Cav1.1突变引起的恶性高热综合征的机制，并利用人类其他基因连锁的新发现。调查范围包括：MH小鼠的广泛表型研究，MH小鼠和MHS人类肌肉中钙离子和钠离子动态平衡的研究以及TRPC的重要性(项目1)，RyRI功能研究，MHS突变如何导致翻译后修饰、线粒体适应性和代谢异常(项目2)，RyR1和CaVI.1之间正常相互作用的中断如何导致MH易感动物和患者的钙离子调节失调(项目3)，以及MH突变对肌肉细胞生理的影响(项目1、2和3)。我们在前一个资助期的研究得出了一个适用于任何和所有MH突变的统一的一般假设：MH是由RyRI的一级结构变化引起的，或者是由Cavl.1或其他与RyR1密切相关的蛋白质的突变间接引起的RyRI的结构变化(Casq1基因缺失小鼠的MH样表型证明了这一点)。所有PPG参与者都要研究的一个变革性概念是，Cav1.1f-RyR1双向信号的缺陷是导致所有MH易感性和进行性肌肉损伤的常见汇聚通路。这个节目的重点是紧密联系在一起的。所有三个项目都将：1.检查性别和MH外显率之间的关系，2.在人类肌肉中验证小鼠模型的病理学。3.确定MHS突变的后遗症是否可以通过减少肌膜钙内流、减少RyR1泄漏、增加肌浆网钙负荷或清除ROS产生的脂质过氧化来减少或预防。4.利用从核心C的发现，建立新发现的不在RyR1或Cav1.1中的突变扰乱RyR1和DHPR之间的正常双向信号传递的机制，从而导致共同的级联反应导致MHS及其相关病理，每种机制都利用各自独特的专业知识。通过这种方式，我们保证，结果将是整个计划大于各个部分的总和。

DESCRIPTION (provided by applicant): The long-term goal of this multicenter PPG is to define the mechanisms responsible for the malignant hyperthermia syndrome caused by mutations in RyR1 and Cav1.1 as well as leveraging new discovery of other gene linkage in humans. The scope of investigations will range from extensive phenotyping of MH mice, studies of Ca2+ and Na+ homeostasis in muscle from MH mice and MHS humans and the importance of TRPCs (Project 1), studies of RyRI function, how MHS mutations cause posttranslational modifications, mitochondrial adaptations and metabolic abnormalities (Project 2), and how disruption of the normal interactions between RyR1 and CaVI.1 lead to Ca2+ dysregulation in MH susceptible animals and patients (Project 3), and the influence of MH mutations on the cellular physiology of muscle (Projects 1, 2, & 3). Our research in the previous funding period has led to a unified general hypothesis applicable to any and all MH mutations: MH is caused by primary structural changes in RyRI, or by structural changes in RyRI induced indirectly by a mutation in Cavl.1 or another protein closely associated with RyR1 (as demonstrated by an MH like phenotype in Casq1 null mice). A transformative concept to be investigated by all PPG participants is that a defect in Cav1.1 f-RyR1 bidirectional signaling is a common convergent pathway leading to all MH susceptibility and progressive muscle damage. The focus of this program is tightly linked. All 3 Projects will: 1. Examine the relationship between gender and MH penetrance, 2. Validate the pathology in mouse models in human muscle. 3. Determine if the sequelae of MHS mutations can be reduced or prevented by genetic/pharmacological manipulations that decrease sarcolemmal Ca2+ entry, reduce RyR1 leak, increase SR Ca2+ load or scavenge lipid peroxides resulting from ROS production. 4. Using discovery from Core C establish the mechanisms by which newly discovered mutations not in RyR1 or Cav1.1 disrupt the normal bidirectional signaling between RyR1 and the DHPR leading to a common cascade causing MHS and its associated pathology, each using their unique expertise. In this way we assure that the outcome will be that the whole of this Program is greater than the sum of the individual parts.