MG53-mediated membrane repair in muscle physiology and disease

MG53 介导的肌肉生理学和疾病中的膜修复

• 批准号: 9103694
• 负责人: Jianjie Ma
• 金额: $ 44.9万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9103694
• 关键词: Acute; Affect; Animals; Area; Biochemical; Biological; Biological Assay; Biology; Biomedical Research; Blood; Blood Circulation; Canis familiaris; Cell membrane; Cell physiology; Cells; Chemistry; Chronic; Clinical Research; Cysteine; Data; Development; Disease; Dose; Excretory function; Extracellular Space; Family suidae; Functional disorder; Funding; Future; Goals; Human; Imaging Device; Immune response; Injury; Kidney; Leucine Zippers; Lipids; Mediating; Membrane; Metabolic Diseases; Metabolic stress; Modeling; Molecular; Molecular Motors; Mus; Muscle; Muscle Cells; Muscle Fibers; Muscular Dystrophies; Myopathy; Organ; Pathology; Pathway interactions; Physiological; Physiology; Polymerase; Process; Production; Proteins; Rattus; Reagent; Recombinants; Regenerative Medicine; Safety; Serum; Signal Pathway; Signal Transduction; Site; Stream; Stress; Testing; Therapeutic; Therapeutic Agents; Tissues; Transcript; Transgenic Mice; Translating; Treatment Efficacy; Vesicle; biochemical tools; extracellular; gene repair; human disease; improved; injured; injury and repair; intravenous administration; mdx mouse; mouse model; non-muscle myosin; novel; paracrine; pre-clinical; public health relevance; receptor; release factor; repaired; restoration; scale up; signal processing; tissue repair; trafficking; translational approach

 DESCRIPTION (provided by applicant): Cell membrane repair is an important aspect of normal physiology, and disruption of this process can result in pathophysiology in a number of human diseases including muscular dystrophy. We previously identified MG53 as an essential component of the cell membrane repair machinery. During the last funding period, we showed that critical cysteine residues and leucine-zipper motifs in MG53 participate in the nucleation process of cell membrane repair; non-muscle myosin type IIa (NM-IIa) acts as a molecular motor to transport MG53- containing vesicles toward the injury site; and PTRF enables anchoring and targeting of the MG53-repair machinery at the injured membrane. In addition to the intracellular action of MG53, injury to the cell membrane exposes a signal that can be detected by circulating MG53, allowing recombinant human (rh)MG53 protein to repair membrane damage when provided in the extracellular space. To develop MG53 as a potential therapeutic agent for treatment of muscle diseases, we have established the chemistry, manufacture and control (CMC) process for scale-up production of rhMG53 to support our pre-clinical and future clinical studies. Clearly, our translational approach cannot proceed without understanding the cellular processes that underlie the control of MG53 in circulation and the mechanistic action of extracellular MG53 in tissue protection. Specifically, a) how does circulating MG53 recognize the tissue injury site to facilitate protection against muscle injury an improve its survival under stress conditions? b) what are the cellular processes that control secretion, transport and clearance of MG53 in blood circulation? c) can sustained elevation of circulating MG53 provide beneficial effects to ameliorate the chronic process of muscular dystrophy? We have recently established a transgenic mouse model with controlled secretion of MG53 in circulation that can be used to examine the function for MG53 in protection against muscle injury in physiological and pathological conditions. This renewal application will focus on testing the hypothesis that "MG53 in circulation protects muscle injury through membrane-delimited signaling pathways, and controlling MG53 secretion, transport and clearance from the blood stream may provide alternative ways for treatment of degenerative muscular diseases". We propose to test the concept that muscle is a paracrine organ that secretes MG53 for tissue protection and renal-mediated excretion of MG53 is a key factor that regulates MG53 levels in circulation. Our transgenic mouse model allows for tailored control of MG53 secretion, providing ways to examine the efficacy for circulating MG53 in ameliorating the pathology of muscular dystrophy in the mdx mice, as well as for evaluating the safety profile for sustained MG53 in affecting other organ functions.

 描述（由申请人提供）：细胞膜修复是正常生理学的一个重要方面，该过程的破坏可能导致包括肌营养不良在内的许多人类疾病的病理生理学。在上一个资助期间，我们证明了MG53中关键的半胱氨酸残基和亮氨酸拉链基序参与了非肌肉肌球蛋白类型的成核过程； IIa (NM-IIa) 充当分子马达，将含有 MG53 的囊泡运输至损伤部位；PTRF 能够将 MG53 修复机制锚定并靶向受损膜。细胞膜暴露出可通过循环 MG53 检测到的信号，从而使重组人 (rh)MG53 蛋白在细胞外空间中修复膜损伤。 MG53作为治疗肌肉疾病的潜在治疗剂，我们已经建立了rhMG53放大生产的化学、制造和控制（CMC）工艺，以支持我们的临床前和未来的临床研究。显然，我们的转化方法无法继续进行。不了解循环中 MG53 控制的细胞过程以及细胞外 MG53 在组织保护中的机制。 b) 控制血液循环中 MG53 的分泌、运输和清除的细胞过程是什么？ c) 循环中 MG53 的持续升高可以对改善肌营养不良症的慢性过程产生有益的作用吗？一种在循环中控制分泌 MG53 的转基因小鼠模型，可用于检查 MG53 在生理和病理条件下防止肌肉损伤的功能。本次更新应用将重点测试“MG53 在体内”的假设。循环通过膜界定的信号通路保护肌肉损伤，控制 MG53 的分泌、运输和血流清除可能为治疗退行性肌肉疾病提供替代方法。”我们建议测试肌肉是分泌 MG53 的旁分泌器官的概念。组织保护和肾脏介导的 MG53 排泄是调节循环中 MG53 水平的关键因素，我们的转基因小鼠模型允许对 MG53 分泌进行定制控制，从而提供了检查功效的方法。循环 MG53 改善 mdx 小鼠肌营养不良的病理学，以及评估持续 MG53 影响其他器官功能的安全性。