Mechanisms of Muscle Inflammation in Muscular Dystrophy

描述(由申请人提供)：炎症反应与各种肌肉营养不良有关，并加剧疾病的进展。特别是，缺铁性肌营养不良症已被发现表现出广泛的肌肉炎症。以前的研究证实了去铁蛋白在质膜修复中的作用。我们和其他研究小组最近证实，包括补体途径和NLRP3(节点样受体家族，含有3个吡咯域)在内的天然免疫系统在缺铁蛋白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不是很清楚。这项研究计划的长期目标是了解干扰素缺乏性肌营养不良症肌肉炎症的分子机制，并探索以炎症信号通路为靶点治疗该疾病的可能性。我们的初步研究发现，囊泡(尤其是由带电脂质组成的囊泡)强烈地诱导IL-1？巨噬细胞通过激活NLRP3炎症体进行分泌。这一观察结果使我们假设，从铁蛋白缺乏的肌肉中泄漏出来的细胞内小泡激活了NLRP3炎症体，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源性小泡的反应、操纵NLRP3炎症体成分的表达以及体外和体内动物模型研究，显著促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了解。这些数据将开始确定调节炎症反应的潜在治疗靶点，从而治疗与膜修复缺陷相关的疾病。

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.