Intracellular calcium leak and muscle function

细胞内钙渗漏与肌肉功能

• 批准号: 7991433
• 负责人: ANDREW Robert MARKS
• 金额: $ 36.23万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7991433
• 关键词: Adverse effects; Affinity; Animal Model; Arrhythmia; Binding; Calcium; Calpain; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cessation of life; Complex; Congenital Heart Defects; Convulsants; Defect; Development; Disease model; Duchenne muscular dystrophy; Dystrophin; Exercise; Exhibits; Functional disorder; Glycoproteins; Heart; Heart failure; Hereditary Disease; Histology; Human; Immunosuppressive Agents; Individual; Laboratories; Lead; Link; Mediating; Membrane; Modeling; Molecular; Morbidity - disease rate; Movement; Mus; Muscle; Muscle Fibers; Muscle Weakness; Muscle function; Muscular Dystrophies; Mutation; Myocardium; Pathology; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Phase II Clinical Trials; Phenotype; Play; Property; Protein Isoforms; Quality of life; Role; RyR1; RyR2; Ryanodine Receptor Calcium Release Channel; Ryanodine Receptors; Sarcoglycans; Skeletal Muscle; Steroid therapy; Striated Muscles; Tacrolimus Binding Protein 1A; Testing; base; design; drinking water; gene replacement; improved; innovation; mdx mouse; mouse model; muscular dystrophy mouse model; new therapeutic target; novel; novel therapeutic intervention; outcome forecast; prevent; public health relevance; small molecule; sudden cardiac death; therapeutic target; therapy development

DESCRIPTION (provided by applicant): Disruption of the dystrophin-sarcoglycan complex (DGC) has been identified as the molecular basis for impaired sarcolemmal membrane integrity and increased cytosolic Ca2+ concentration [Ca2+]i in some muscular dystrophies (MDs). This increased [Ca2+]i contributes to myofiber death via activation of calpains (Ca2+-dependent neutral proteases). Moreover, the rate of Ca2+ sparks significantly increases in dystrophic myofibers, consistent with defective "leaky" SR Ca2+ release channels. Indeed, recent studies have identified RyR1 mutations that are genetically linked to MDs. We recently showed that S-nitrosylation of the type 1 ryanodine receptor (RyR1) in skeletal muscle causes FKBP12 (calstabin1) depletion from the channel complex resulting in SR Ca2+ leak that contributes to muscle weakness and damage in the murine mdx model of Duchenne muscular dystrophy. Treatment with S107, a novel small molecule derived from 1,4-benzothiazepines, that inhibits calstabin-1 depletion from the RyR1 complex, improved exercise capacity, muscle force and reduced muscle damage in dystrophic mice. The applicant proposes to test the hypothesis that "leaky" RyR1 and RyR2 channels due to hypernitrosylation of the channels are a common feature of MDs that involve disruption of the DCG. Furthermore, by preventing RyR1 and RyR2 leak using a novel compound, S107, the applicant will seek to reduce muscle damage, cardiac abnormalities, and improve exercise capacity in murine models of MD. The proposed studies are significant because they may identify a novel mechanism underlying intracellular Ca2+ leak that contributes to pathology in MD and could be a therapeutic target in patients. PUBLIC HEALTH RELEVANCE: Muscular Dystrophy (MD) is a heterogeneous, genetic disease characterized by progressive weakness and degeneration of striated muscle, in particular the skeletal muscles that control movement. Despite important advances that have elucidated molecular mechanisms, therapy for most forms of MD remains supportive and prognosis is grave for many patients. Moreover, the side effects of the current therapies (steroids, immunosuppressants and anti-convulsants) can add to the morbidity of MD. It is possible that an improved understanding the pathophysiology of MD could lead to the development novel therapeutic approaches that could improve quality of life and prolong survival. This might be particularly important as definitive treatments such as gene replacement are being developed. The present project is designed to test a novel therapeutic target for MD, "leaky" ryanodine receptor/calcium release channels, and determine whether a new class of drugs called rycals that fix the leak in the channel improve exercise capacity in MD and prevent muscle damage in mouse models.

描述（由申请人提供）：已确定肌营养不良蛋白-肌聚糖复合物（DGC）的破坏是某些肌营养不良症（MD）中肌膜完整性受损和胞质Ca 2+浓度[Ca 2 +]i增加的分子基础。这种增加的[Ca 2 +]i通过钙蛋白酶（Ca 2+依赖性中性蛋白酶）的激活而导致肌纤维死亡。此外，在营养不良的肌纤维中，Ca 2+火花的速率显著增加，这与有缺陷的“渗漏”SR Ca 2+释放通道一致。事实上，最近的研究已经确定了与MD遗传相关的RyR 1突变。我们最近发现，骨骼肌中1型ryanodine受体（RyR 1）的S-亚硝基化导致FKBP 12（calstabin 1）从通道复合物中耗尽，导致SR Ca 2+泄漏，导致Duchenne肌营养不良症鼠mdx模型中的肌无力和损伤。用S107治疗，一种来自1，4-苯并硫氮杂卓的新型小分子，可抑制RyR 1复合物中的calstabin-1消耗，改善营养不良小鼠的运动能力，肌肉力量和减少肌肉损伤。申请人提出检验以下假设：由于通道的高亚硝基化导致的“泄漏”RyR 1和RyR 2通道是涉及DCG破坏的MD的共同特征。此外，通过使用新型化合物S107防止RyR 1和RyR 2泄漏，申请人将寻求减少MD鼠模型中的肌肉损伤、心脏异常并改善运动能力。拟议的研究是有意义的，因为它们可以确定一种新的机制，细胞内Ca 2+泄漏，有助于病理学在MD和可能是一个治疗目标的患者。 公共卫生关系：肌营养不良症（MD）是一种异质性遗传疾病，其特征在于横纹肌（特别是控制运动的骨骼肌）的进行性无力和变性。尽管已经阐明了分子机制的重要进展，但大多数形式的MD的治疗仍然是支持性的，并且许多患者的预后是严重的。此外，目前的治疗（类固醇，免疫抑制剂和抗惊厥药）的副作用可以增加MD的发病率。这是可能的，一个更好的理解MD的病理生理可能导致开发新的治疗方法，可以改善生活质量和延长生存期。这一点可能特别重要，因为基因替代等确定性治疗方法正在开发中。本项目旨在测试MD的一种新的治疗靶点，“泄漏”ryanodine受体/钙释放通道，并确定是否有一类称为rycals的新药物可以修复通道中的泄漏，从而改善MD的运动能力并防止小鼠模型中的肌肉损伤。