Intracellular calcium leak and muscle function

细胞内钙渗漏与肌肉功能

• 批准号: 8468120
• 负责人: ANDREW Robert MARKS
• 金额: $ 33.04万
• 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/8468120
• 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; 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.

描述(申请人提供)：肌营养不良蛋白-肌聚糖复合体(DGC)的破坏已被确认为某些肌营养不良症(MD)肌膜完整性受损和胞浆[钙]i升高的分子基础。这种增加的[Ca~(2+)]i通过激活钙离子依赖的中性蛋白水解酶(CaP)而导致肌纤维死亡。此外，营养不良肌纤维中钙离子的激发率显著增加，这与存在缺陷的“泄漏”的肌浆网钙离子释放通道相一致。事实上，最近的研究已经确定了RyR1突变与MDS有基因联系。我们最近发现，在Duchenne肌营养不良的小鼠MDX模型中，骨骼肌中1型ryanodine受体(RyR1)的S亚硝化导致FKBP12(钙稳定蛋白1)从通道复合体中耗尽，导致肌浆网钙泄漏，从而导致肌肉无力和损伤。S107是一种源自1，4-苯并硫氮卓类药物的新型小分子，可抑制RyR1复合体中Calstain-1的耗竭，改善营养不良小鼠的运动能力、肌力和减少肌肉损伤。申请人建议检验这样一种假设，即由于通道的高亚硝化而导致的RyR1和RyR2通道的“泄漏”是涉及DCG中断的MD的共同特征。此外，通过使用一种新的化合物S107防止RyR1和RyR2的泄漏，申请人将寻求减少MD小鼠模型的肌肉损伤、心脏异常和提高运动能力。提出的研究具有重要意义，因为它们可能识别导致MD病理的细胞内钙离子泄漏的新机制，并可能成为患者的治疗靶点。