Mechanisms of Muscle Inflammation in Muscular Dystrophy

描述（由申请人提供）：炎症反应与各种肌营养不良症相关，并加剧疾病进展。特别是，已发现dysferlin缺陷型肌营养不良症表现出广泛的肌肉炎症。先前的研究确定了dysferlin在质膜修复中的作用。我们和其他研究小组最近证明，先天免疫系统，包括补体途径和NLRP 3（Nod样受体家族，pyrin结构域包含3）炎性体在dysferlin缺乏的肌肉中被激活。然而，启动和维持免疫激活的分子机制还没有很好地理解。这项研究计划的长期目标是了解dysferlin缺陷型肌营养不良症肌肉炎症的分子机制，并探索靶向炎症信号通路治疗这种疾病的治疗潜力。我们的初步研究发现，囊泡（特别是，囊泡组成的带电脂质）强烈诱导IL-1？通过激活NLRP 3炎性体从巨噬细胞分泌。这一观察结果使我们假设，从dysferlin缺乏的肌肉中漏出的细胞内囊泡激活了NLRP 3炎性体，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囊泡的反应，操纵NLRP 3炎性体组分的表达以及离体和体内动物模型研究，显着推进对具有膜修复缺陷的骨骼肌与免疫系统之间相互作用的理解。这些数据将开始定义用于调节炎症反应的潜在治疗靶点，从而治疗与有缺陷的膜修复相关的疾病。

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.