Targeting Membrane Repair in Muscular Dystrophy

肌营养不良症的靶向膜修复

基本信息

批准号：
8727259
负责人：
Noah Weisleder
金额：
$ 33.96万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-21 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8727259
关键词：
Acute Address Affect Basic Science Binding Biological Assay Biology Blood Cell Death Cell Survival Cell membrane Cell physiology Cells Cessation of life Child Complex DYSF gene Data Defect Deformity Direct Lytic Factors Disease Duchenne muscular dystrophy Dystroglycan Dystrophin Exposure to Extracellular Space Foundations Functional disorder Hereditary Disease Human In Vitro Inherited Injury Intravenous Joints Knockout Mice Knowledge Life Link Mechanical Stress Medical Membrane Methodology Modeling Molecular Muscle Muscle Cells Muscle Fibers Muscle function Muscular Dystrophies Mutation Necrosis Pathologic Pathology Patients Phosphatidylserines Physiological Process Protein Binding Proteins Recombinants Research Rodent Model Role Severities Signal Transduction Site Skeletal Muscle Striated Muscles Subcutaneous Injections TRIM Family Technology Testing Therapeutic Therapeutic Agents Therapeutic Intervention Transgenic Organisms Translating Utrophin Vertebral column Vesicle base caveolin-3 cell type design extracellular immunogenicity improved in vivo insight mdx mouse mouse model muscular structure novel novel therapeutic intervention novel therapeutics overexpression prevent repaired research study seal therapeutic target trafficking wasting

项目摘要

DESCRIPTION (provided by applicant): Duchenne muscular dystrophy (DMD) and other dystrophies arising from mutations in the dystrophin/dystroglycan complex produce pathology, at least in part, due to sarcolemmal membrane fragility. Several other forms of muscular dystrophy have been linked to defective membrane repair including those linked to mutations in caveolin-3 (Cav3) and dysferlin in human patients. A therapeutic approach to increase the capacity of muscle cells to reseal their membranes following physiological levels of mechanical stress could address both of these mechanisms leading to improvement of muscular dystrophy pathology. We recently discovered that mitsuguimin 53 (MG53), a muscle-specific TRIM-family protein, is an essential component of the acute membrane repair machinery. MG53 nucleates recruitment of intracellular vesicles to the injury site for membrane patch formation. We found that MG53 can interact with dysferlin to facilitate its membrane repair function, and some of the membrane repair defects in muscular dystrophy are associated with altered interaction between MG53, caveolin-3 and dysferlin. In new data presented in this application, we find that acute injury many cell types leads to exposure of a phosphatidylserine (PS) signal to the extracellular space that can be detected by purified recombinant human MG53 protein (rhMG53), allowing rhMG53 to locate to the injury sites and increase the capacity of targeted cells to repair membrane damage. These findings led us to hypothesize that: rhMG53 and native MG53 can bind to PS that flows through membrane disruptions to increase the membrane repair capacity of cell membranes. This action would allow rhMG53 to act as a therapeutic agent for the treatment of muscular dystrophy. We will test this possibility with two specific Aims. Aim 1 will establish the mechanism(s) contribute to the extracellular action of rhMG53 in membrane resealing. Aim 2 will test if rhMG53 can provide therapeutic benefit in a faithful mouse model of DMD. Our studies here provide important steps forward in understanding the mechanisms of extracellular MG53 action in membrane repair and can help to establish if rhMG53 could effectively treat a model of muscular dystrophy. The ability for rhMG53 to increase membrane repair in non-muscle cells suggests that rhMG53 may act as a platform technology that could target a number of different disease states where compromised membrane integrity and/or necrotic cell death contribute to the underlying pathology.

描述（由申请人提供）：杜氏肌营养不良症（DMD）和由肌营养不良蛋白/肌营养不良聚糖复合物突变引起的其他营养不良至少部分由于肌膜脆性而产生病理。其他几种形式的肌营养不良症与膜修复缺陷有关，包括与人类患者中的 Caveolin-3 (Cav3) 和 Dysferlin 突变有关的肌营养不良症。增加肌肉细胞在机械应力的生理水平后重新密封其细胞膜的能力的治疗方法可以解决这两种机制，从而改善肌营养不良症的病理学。我们最近发现 mitsuguimin 53 (MG53) 是一种肌肉特异性 TRIM 家族蛋白，是急性膜修复机制的重要组成部分。 MG53 将细胞内囊泡聚集到损伤部位以形成膜片。我们发现MG53可以与dysferlin相互作用以促进其膜修复功能，并且肌营养不良症中的一些膜修复缺陷与MG53、caveolin-3和dysferlin之间相互作用的改变有关。在本申请中提供的新数据中，我们发现许多细胞类型的急性损伤会导致磷脂酰丝氨酸（PS）信号暴露于细胞外空间，该信号可以通过纯化的重组人MG53蛋白（rhMG53）检测到，从而使rhMG53能够定位到损伤部位并增加靶细胞修复膜损伤的能力。这些发现使我们推测：rhMG53和天然MG53可以与流经膜破裂的PS结合，从而增加细胞膜的膜修复能力。这一作用将使 rhMG53 成为治疗肌营养不良症的药物。我们将通过两个具体目标来测试这种可能性。目标 1 将建立 rhMG53 在膜重新密封中的细胞外作用的机制。目标 2 将测试 rhMG53 是否可以在忠实的 DMD 小鼠模型中提供治疗效果。我们的研究为理解细胞外 MG53 在膜修复中的作用机制迈出了重要的一步，并有助于确定 rhMG53 是否可以有效治疗肌营养不良症模型。 rhMG53 增强非肌肉细胞膜修复的能力表明，rhMG53 可能作为一种平台技术，可以针对多种不同的疾病状态，在这些疾病状态中，膜完整性受损和/或坏死细胞死亡会导致潜在的病理学。