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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要杜氏肌营养不良症 (DMD) 是最常见的营养不良形式，是由基因突变引起的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-糖蛋白复合物的丢失，保护肌肉细胞的肌膜免受收缩引起的损伤。DMD 的特点是严重。肌肉无力和消耗，导致早期危及生命的心脏和呼吸功能障碍在提高受影响个人的生活质量方面已经取得了进展；然而，情况却在恶化；心脏功能的恶化发展为扩张型心肌病并随后出现心力衰竭，这是主要的 DMD 个体的死亡原因当前的应用重点是了解心脏疾病。与肌营养不良症相关的机制并测试已知可改善的新疗法我们的研究小组率先在 DMD 骨骼肌疾病方面取得了多项重要发现。我们已经证明了肌跨蛋白的功能，它是肌营养不良蛋白-糖蛋白复合物的一个组成部分。 mdx 小鼠骨骼肌中轻度肌跨过度表达，该小鼠具有小鼠突变肌营养不良蛋白基因，通过稳定称为肌营养不良蛋白的蛋白质复合物的表达来拯救肌营养不良症事实上，肌营养不良蛋白-糖蛋白复合物在功能上类似于肌营养不良蛋白-糖蛋白复合物。我们的研究揭示了 sarcospan 在确定细胞表面表达方面的类似伴侣功能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 整合素）已知可改善 DMD 小鼠模型的疾病，Sarcospan 会激活 Akt。促进肌肉生长和再生的信号通路，为营养不良者提供进一步的益处拟议的实验将测试将肌跨引入心肌是否会改善。我们的研究将检查 DMD 中的层粘连蛋白结合。相关的心肌病并揭示肌跨是否影响调节层粘连蛋白结合受体在我们的初步数据中，我们揭示了肌跨缺陷的新心脏表型。小鼠，我们将研究肌跨是否对多种心脏挑战具有心脏保护作用。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 sarcospan 的治疗的见解。