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（由适用提供）：细胞膜修复是正常生理学的重要方面，而这种过程的破坏可能会导致许多人类疾病（包括肌肉营养不良）的病理生理学。我们先前将MG53确定为细胞膜修复机械的重要组成部分。在最后一个资金期间，我们表明临界半胱氨酸在MG53中保留和亮氨酸Zipper基序参与细胞膜修复的成核过程。非肌肉肌球蛋白型IIA（NM-IIA）充当分子运动，可将含有MG53的蔬菜运输到损伤部位； PTRF可以在受伤的膜上锚定和靶向MG53修复机械。除了MG53的细胞内作用外，细胞膜的损伤还暴露了一个可以通过循环MG53检测到的信号，从而使重组人（RH）MG53蛋白在细胞外空间中提供时可修复膜损伤。为了开发MG53作为治疗肌肉疾病的潜在治疗剂，我们建立了用于扩大RHMG53的化学，制造和对照过程（CMC）过程，以支持我们的临床前和未来的临床研究。显然，如果不了解MG53在循环中控制和细胞外MG53在组织保护中控制MG53的基础的细胞过程，我们的翻译方法无法进行。具体而言，a）循环MG53如何识别组织损伤部位以促进防止肌肉损伤的保护在压力条件下的生存改善？ 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MG53的持续升高可以提供有益的效果，以改善肌肉营养不良的慢性过程？我们最近建立了一种具有控制循环中MG53分泌的转基因小鼠模型，该模型可用于检查MG53的功能，以防止在物理和病理条件下防止肌肉损伤。这种更新的应用将着重于检验以下假设：“循环中的MG53通过膜延伸的信号通路保护肌肉损伤，并控制血流中的MG53分泌，运输和清除率可能为治疗退行性肌肉疾病的治疗提供替代方法”。我们建议测试肌肉是一种偏眼烯的器官，它将MG53秘密进行组织保护和肾脏介导的极端MG53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分泌进行量身定制的控制，从而提供了检查MDX小鼠中循环MG53的有效性，并评估MG53在影响其他器官功能方面持续的MG53的安全性。