Basis of Muscle Dysfunction in Malignant Hyperthermia and Central Core Disease

描述（由申请人提供）：RYR 1基因的突变是几种使人衰弱、危及生命的肌肉疾病的基础。在本申请中，我们提出使用具有敲入突变成RyR 1（Y 524 S）的小鼠模型，其具有这些疾病中的三种的特征：恶性高热（MH）、热/运动诱导的劳力性横纹肌溶解症（ER）和中央核心疾病（CCD）。我们的长期目标是确定与这些疾病相关的肌肉功能下降的机制，并开发新的干预措施。我们对当前提案的总体工作假设是RyR 1中的Y 524 S突变增加了兴奋-收缩偶联（ECC）和RyR 1 Ca 2+泄漏的温度敏感性，产生MH反应并驱动氧化应激和线粒体破坏，导致肌病。我们的具体目标是：（1）阐明CaV1.1介导的Ca ~（2+）内流在MH反应和肌病发展中的作用;（2）阐明YS小鼠核心形成的机制;（3）确定能量敏感激酶AMPK的激活剂（AICAR）阻止MH反应的机制，并评估AICAR减缓YS小鼠肌病发展的能力;和4）确定蛋白FKBP 12的非免疫抑制配体阻止MH反应的机制，并评估SLF对YS小鼠肌病的作用。拟议的工作是非常重要的，因为我们直接耦合疾病过程的基础路径的描绘与新的治疗干预措施，具有不同的作用机制的发展，允许一些灵活性，以定制治疗策略与MH和CCD相关的不同突变。这项研究之所以具有创新性，是因为：1）范式转变假设; 2）独特的小鼠模型; 3）尖端技术; 4）以前从未提出过治疗MH或其他RyR 1相关肌病的治疗干预措施。

DESCRIPTION (provided by applicant): Mutations in the RYR1 gene underlie several debilitating, life-threatening muscle diseases. In this application we are proposing to use a mouse model with a knockin mutation into RyR1 (Y524S) that has features of three of these disorders: malignant hyperthermia (MH) heat/exercise-induced exertional rhabdomyolysis (ER) and central core disease (CCD). Our long term goals are to define the mechanisms that underlie the decline in muscle function associated with these diseases and to develop new interventions. Our overall working hypothesis for the current proposal the Y524S mutation in RyR1 increases the temperature sensitivity of both excitation-contraction coupling (ECC) and RyR1 Ca2+ leak, producing the MH response and driving oxidative stress and mitochondrial destruction that leads to the myopathy. Our specific aims are to: 1) Elucidate the role of Ca2+ influx via CaV1.1 in the MH response and the development of the myopathy; 2) Delineate the mechanisms of core formation in YS mice; 3) Define the mechanism by which an activator (AICAR) of the energy sensing kinase AMPK prevents the MH response and evaluate AICAR's ability to slow the development of the myopathy in YS mice; and 4) Define the mechanism by which a non-immunosuppressive ligand for the protein FKBP12 prevents the MH response and evaluate SLF's effect on the myopathy in YS mice. The proposed work is highly significant because we directly couple the delineation of pathways underlying disease processes with the development of novel therapeutic interventions that have distinct mechanisms of action, allowing for some flexibility to tailor treatment strategies to different mutations associated with MH and CCD. The proposed research is innovative because of: 1) paradigm shifting hypotheses; 2) unique mouse models, 3) cutting edge technologies, and 4) therapeutic interventions never previously proposed as treatments for MH or other RyR1-linked myopathies.