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：
8548229
负责人：
Noah Weisleder
金额：
$ 32.87万
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/8548229
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）：Duchenne肌肉营养不良（DMD）和其他营养不良蛋白/肌营养不良肿瘤复合物引起的营养不良，至少部分是由于肌膜膜膜脆弱性引起的。其他几种形式的肌营养不良症与膜修复有缺陷有关，包括与小窝蛋白3（CAV3）和人类患者dysferlin相关的肌肉修复。一种治疗方法，可在生理压力下增加肌肉细胞重新密封其膜的能力，这可以解决这两种机制，从而改善肌营养不良的病理。我们最近发现，肌肉特异性的蛋白质蛋白（MG53）是急性膜修复机械的重要组成部分。 MG53将细胞内囊泡募集到损伤部位以形成损伤部位。我们发现MG53可以与Dysferlin相互作用以促进其膜修复功能，并且肌肉营养不良中的某些膜修复缺陷与MG53，Caveolin-3和Dysferlin之间的相互作用改变有关。在本应用程序中介绍的新数据中，我们发现急性损伤许多细胞类型导致磷脂酰丝氨酸（PS）信号暴露于细胞外空间，可以通过纯化的重组人MG53蛋白（RHMG53）检测到，可将RHMG53置于损伤位点并增加靶向细胞的能力。这些发现导致我们假设：RHMG53和天然MG53可以与PS结合，该PS流经膜破坏以增加细胞膜的膜修复能力。该动作将使RHMG53充当治疗肌肉营养不良的治疗剂。我们将以两个具体目标测试这种可能性。 AIM 1将建立在膜重新密封中RHMG53的细胞外作用的机制。 AIM 2将测试RHMG53是否可以在忠实的DMD鼠标模型中提供治疗益处。我们在这里的研究为了解膜修复中细胞外MG53作用的机制提供了重要步骤，并可以帮助确定RHMG53是否可以有效地治疗肌营养不良模型。 RHMG53在非肌肉细胞中增加膜修复的能力表明，RHMG53可能充当一种平台技术，该技术可以针对许多不同疾病状态，在这些疾病状态下，膜完整性受损和/或坏死细胞死亡会影响潜在的病理学。