Understanding the mechanism and role of cell membrane repair in Miyoshi Myopathy

了解细胞膜修复在三好肌病中的机制和作用

基本信息

批准号：
9534519
负责人：
JYOTI K JAISWAL
金额：
$ 38.44万
依托单位：
CHILDREN'S RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-02 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9534519
关键词：
Address Antioxidants B-Lymphocytes Cell Survival Cell membrane Cells Cholesterol Creatine Kinase Cytoskeleton DYSF gene Development Disease Endosomes Enzymes Excision Exocytosis F-Actin Generations Genes Human Injury Intervention Knowledge Limb-Girdle Muscular Dystrophies Lipid Bilayers Lipids Liver Lysosomes Maintenance Mediating Membrane Membrane Fusion Membrane Lipids Membrane Proteins Monitor Mus Muscle Muscle Cells Muscle Fibers Muscular Dystrophies Mutation Myopathy Normal Cell Oxides Patients Pharmaceutical Preparations Process Proteins Recombinants Role Sarcolemma Serum Site Skeletal Muscle Sphingomyelinase Sphingomyelins Testing Therapeutic Therapeutic Intervention Vitamin E Vitamins acid sphingomyelinase cell injury combinatorial dysferlinopathies extracellular extracellular vesicles improved in vivo injured insight live cell imaging mouse model novel novel therapeutics oxidation oxidized lipid pre-clinical preclinical efficacy prevent repaired

项目摘要

Summary Many muscular dystrophies are caused by mutation in proteins that compromise the stability and integrity of the muscle sarcolemma, which results in high serum level of muscle enzymes such as Creatine Kinase. Understanding the mechanism by which healthy myofibers maintain their sarcolemmal integrity would enable development of new therapies for these muscular dystrophies. Miyoshi myopathy (MM) and limb girdle muscular dystrophy (LGMD) 2B, caused by mutations in dysferlin gene are such diseases. We have identified that loss of sarcolemmal integrity in LGMD2B muscle fibers is due to the delay in fusion of lysosome with the injured sarcolemma. This causes a delay in injury-triggered secretion of the lysosomal enzyme acid sphingomyelinase. Providing extracellular sphingomyelinase reverses the repair deficit and offers a potential therapy for LGMD2B. However, the mechanism by which alteration in sphingomyelin and other cell membrane lipids facilitates repair of injured muscle cell membranes has not been fully elucidated. This proposal aims to identify how lipids and lipid modifying enzymes such as acid sphingomyelinase facilitate maintenance of sarcolemmal integrity and facilitate repair of injured sarcolemma. We will achieve this by visualizing and modifying lipid composition of healthy muscle cell membrane and assess their effect on sarcolemmal integirty. We will also assess how lipids respond are altered in the LGMD2B patient and mouse muscle cells to identify potential therapeutic interventions to address these alterations. One such intervention we have established is the use of acid sphingomyelinase and we will evaluate its preclinical therapeutic potential for LGMD2B. These studies will not only help understand the role of lipids in maintenance of sarcolemmal integrity, but also provide insight into developing novel therapies for muscular dystrophies that move beyond targeting the proteins to also targeting the sarcolemmal lipids.

概括许多肌营养不良症是由蛋白质突变引起的，这些突变损害了肌营养不良症的稳定性和完整性。肌肉肌膜，导致肌酸激酶等肌酶的血清水平升高。了解健康肌纤维维持肌膜完整性的机制将有助于开发针对这些肌肉营养不良症的新疗法。三好肌病 (MM) 和肢带由 Dysferlin 基因突变引起的肌营养不良症 (LGMD) 2B 属于此类疾病。我们已经确定 LGMD2B 肌纤维肌膜完整性的丧失是由于溶酶体与肌纤维融合延迟所致肌膜受伤。这会导致损伤触发的溶酶体酶酸分泌延迟鞘磷脂酶。提供细胞外鞘磷脂酶可逆转修复缺陷并提供潜在的 LGMD2B 的治疗。然而，鞘磷脂和其他细胞膜的改变机制脂质促进受损肌肉细胞膜修复的作用尚未完全阐明。该提案旨在确定脂质和脂质修饰酶（例如酸性鞘磷脂酶）如何促进维持肌膜完整性并促进受损肌膜的修复。我们将通过可视化和改变健康肌肉细胞膜的脂质成分并评估其对肌膜完整性的影响。我们还将评估 LGMD2B 患者和小鼠肌肉细胞中脂质反应如何改变，以确定解决这些变化的潜在治疗干预措施。我们建立的其中一项干预措施是使用酸性鞘磷脂酶，我们将评估其对 LGMD2B 的临床前治疗潜力。这些研究不仅有助于了解脂质在维持肌膜完整性中的作用，而且还提供深入了解开发针对肌营养不良症的新疗法，这些疗法超越了针对蛋白质的目标还针对肌膜脂质。