Restoration of muscle cell adhesion to treat cardiomyopathy in muscular dystrophy

恢复肌细胞粘附以治疗肌营养不良症中的心肌病

• 批准号: 9312863
• 负责人: Rachelle Hope Crosbie
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9312863
• 关键词: AKT Signaling Pathway; Ablation; Actins; Adhesions; Affect; Aging; Binding; Biochemical; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cell Adhesion; Cell membrane; Cell surface; Child; Complex; Cytoskeleton; Data; Deterioration; Development; Dilated Cardiomyopathy; Disease; Disease Progression; Duchenne muscular dystrophy; Dystrophin; Event; Extracellular Matrix; Fibrosis; Functional disorder; Genes; Genetic Transcription; Glycoproteins; Growth; Heart; Heart Diseases; Heart failure; Hereditary Disease; Individual; Inherited; Injury; Integral Membrane Protein; Integrins; Isoproterenol; Laminin; Life; Link; Mechanics; Mediating; Membrane; Molecular; Molecular Chaperones; Mus; Muscle; Muscle Cells; Muscle Contraction; Muscle Weakness; Muscle function; Muscular Atrophy; Muscular Dystrophies; Muscular dystrophy cardiomyopathy; Mutation; Myocardium; Myopathy; Natural regeneration; Outcome; Pathogenesis; Pathologic; Pharmacology; Phenotype; Physiological; Proteins; Proteomics; Quality of life; Research; Respiratory Failure; Role; SSPN gene; Sarcolemma; Skeletal Muscle; Stress; Testing; Therapeutic; Tissues; Transgenic Organisms; Utrophin; Wild Type Mouse; base; constriction; experimental study; heart function; improved; innovation; insight; mdx mouse; mortality; mouse model; overexpression; patient population; preclinical study; prevent; protein complex; receptor binding; respiratory; response; restoration

PROJECT ABSTRACT Duchenne muscular dystrophy (DMD), the most common form of dystrophy, is caused by mutations in the dystrophin gene that result in loss of dystrophin protein and the entire dystrophin-glycoprotein complex, which protects the sarcolemma of muscle cells from contraction-induced injury. DMD is characterized by severe muscle weakness and wasting that leads to life-threatening cardiac and respiratory dysfunction in the early twenties. Progress has been made to enhance the quality of life of affected individuals; however, deterioration of cardiac function progresses to dilated cardiomyopathy with subsequent heart failure and is the primary cause of mortality in DMD individuals. The current application is focused on understanding the cardiac mechanisms associated with muscular dystrophy and testing new treatments that are known to ameliorate DMD skeletal muscle disease. Our research group has pioneered several key discoveries related to the function of sarcospan, an integral component of the dystrophin-glycoprotein complex. We have demonstrated that mild sarcospan over-expression in skeletal muscle of mdx mice, which possess a mutation in the murine dystrophin gene, rescues muscular dystrophy by stabilizing expression of a complex of proteins called the utrophin-glycoprotein complex that is functionally analogous to the dystrophin-glycoprotein complex. In fact, our studies are revealing a chaperone-like function for sarcospan in determining the cell surface expression of laminin-binding adhesion complexes (i.e. dystrophin-glycoprotein complex, utrophin-glycoprotein complex, and α7β1 integrin) that are known to ameliorate disease in DMD mouse models. Sarcospan activates the Akt signaling pathway that promotes muscle growth and regeneration, providing further benefit to dystrophic muscle. The proposed experiments will test whether introduction of sarcospan into heart muscles ameliorates cardiomyopathy associated with muscular dystrophy. Our studies will examine laminin-binding in DMD associated cardiomyopathy and reveal whether sarcospan affects laminin-binding receptors that regulate cardiomyocyte adhesion. In our preliminary data, we reveal a new cardiac phenotype in sarcospan-deficient mice and we will investigate whether sarcospan is cardioprotective to multiple cardiac challenges. The outcomes of the proposal will change our understanding of DMD cardiac pathogenesis and provide necessary insight for development of sarcospan-based treatments.

项目摘要 Duchenne肌营养不良症（DMD）是最常见的营养不良形式，是由 肌营养不良蛋白基因，导致肌营养不良蛋白和整个肌营养不良蛋白-糖蛋白复合物的损失， 保护肌细胞的肌膜免受收缩诱导的损伤。DMD的特征是严重的 肌肉无力和消瘦，导致早期危及生命的心脏和呼吸功能障碍， 二十在提高受影响个人的生活质量方面取得了进展;但是， 心功能的恶化发展为扩张型心肌病，随后发生心力衰竭， DMD患者的死亡原因。目前的应用集中在了解心脏 与肌营养不良症相关的机制，并测试新的治疗方法， DMD骨骼肌疾病。我们的研究小组率先取得了与 肌营养不良蛋白-糖蛋白复合物的组成部分sarcospan的功能。我们已经证明 在mdx小鼠骨骼肌中轻度sarcospan过度表达，mdx小鼠在小鼠中具有突变， 肌营养不良蛋白基因，通过稳定一种称为 肌营养不良蛋白-糖蛋白复合物，其在功能上类似于肌营养不良蛋白-糖蛋白复合物。事实上， 我们的研究揭示了sarcospan在决定细胞表面表达 层粘连蛋白结合粘附复合物（即肌营养不良蛋白-糖蛋白复合物、肌营养不良蛋白-糖蛋白复合物，和 α7β1整联蛋白），其已知在DMD小鼠模型中改善疾病。Sarcosspan激活Akt 促进肌肉生长和再生的信号通路，为营养不良的 肌肉.拟议的实验将测试是否将sarcospan引入心肌改善 与肌营养不良有关的心肌病。我们的研究将探讨层粘连蛋白结合在DMD 相关的心肌病，并揭示是否sarcospan影响层粘连蛋白结合受体， 心肌细胞粘附在我们的初步数据中，我们揭示了一种新的心肌表型， 我们将研究sarcospan是否对多种心脏挑战具有心脏保护作用。的 该提案的结果将改变我们对DMD心脏发病机制的理解，并提供必要的 对开发基于sarcosan的治疗方法的见解。