Mechanisms of Muscle Inflammation in Muscular Dystrophy

肌营养不良症中肌肉炎症的机制

基本信息

批准号：
8847225
负责人：
Renzhi Han
金额：
$ 26.95万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8847225
关键词：
Ablation Animal Model Antibody Formation Antigens Calcium Cations Cell Culture Techniques Cell membrane Cells Charge Chelating Agents DYSF gene Data Defect Disease Disease Progression Encapsulated Exhibits Exposure to Extravasation Family Flow Cytometry Fluorescence Microscopy Generations Genetic Goals Health Histopathology Image Immune system Immunization In Vitro Inflammation Inflammatory Inflammatory Response Interleukin-1 Investigation Knockout Mice Light Lipids Liposomes Lysosomes Measures Mechanical Stress Membrane Microsomes Mitochondria Molecular Mus Muscle Muscular Dystrophies Mutant Strains Mice Outcome Oxidation-Reduction Pathogenesis Pathology Pathway interactions Patients Pilot Projects Regulation Research Research Proposals Role Serum Signal Pathway Signal Transduction Skeletal Muscle Testing Therapeutic Vesicle complement pathway complement system cytokine design dysferlinopathies effective therapy human disease immune activation in vivo inhibitor/antagonist injured interdisciplinary approach macrophage marenostrin mutant novel therapeutics public health relevance receptor recombinase repaired research study response therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Inflammatory response is associated with various muscular dystrophies and exacerbates the disease progression. In particular, dysferlin-deficient muscular dystrophy has been found to exhibit extensive muscle inflammation. Previous studies established a role of dysferlin in plasma membrane repair. We and other groups recently demonstrated that the innate immune system including the complement pathway and the NLRP3 (Nod-like receptor family, pyrin domain containing 3) inflammasome are activated in dysferlin-deficient muscle. However, the molecular mechanisms that initiate and perpetuate the immune activation are not well understood. The long-term goal of this research proposal is to understand the molecular mechanisms of muscle inflammation in dysferlin-deficient muscular dystrophy and explore the therapeutic potential of targeting the inflammatory signaling pathways in the treatment of this disease. Our pilot studies found that vesicles (in particular, the vesicle composed of charged lipids) strongly induce IL-1? secretion from macrophages through activation of the NLRP3 inflammasome. This observation led us to hypothesize that intracellular vesicles leaked out from dysferlin-deficient muscle activates the NLRP3 inflammasome, causing muscle inflammation. Our planned experiments will significantly advance understanding of the interplay between skeletal muscle with membrane repair defect and the immune system by measuring responses of macrophages to skeletal muscle-derived vesicles, manipulating expression of the NLRP3 inflammasome components and ex vivo and in vivo animal model studies. These data will begin to define potential therapeutic targets for regulation of inflammatory responses, thereby treating the diseases associated with defective membrane repair.

描述（由申请人提供）：炎症反应与各种肌肉营养不良有关，并加剧了疾病进展。特别是，dysferlin缺陷肌肉营养不良表现出广泛的肌肉炎症。先前的研究确定了杜塞特林在质膜修复中的作用。我们和其他组最近证明，包括补体途径和NLRP3（点状受体家族，含有3）的先天免疫系统3）在Dysferlin缺陷肌肉中被激活。然而，尚不清楚启动和永久化的分子机制。该研究建议的长期目标是了解dysferlin缺陷肌肉营养不良中肌肉炎症的分子机制，并探索靶向该疾病治疗炎症信号通路的治疗潜力。我们的试点研究发现，囊泡（尤其是由带电脂质组成的囊泡）强烈诱导IL-1？通过激活NLRP3炎性体从巨噬细胞分泌。这一观察结果使我们假设从Dysferlin缺乏的肌肉泄漏出细胞内囊泡会激活NLRP3炎症体，从而导致肌肉炎症。我们计划的实验将通过测量巨噬细胞对骨骼肌衍生的囊泡的反应，操纵NLRP3炎性体组件的表达，以及体内和体内动物模型研究的表达，从而显着提高对骨骼肌肉与膜修复缺陷与免疫系统之间相互作用的了解。这些数据将开始定义用于调节炎症反应的潜在治疗靶标，从而治疗与有缺陷的膜修复相关的疾病。