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症有关，并加剧疾病进展。特别是，异常蛋白缺乏型肌营养不良已被发现表现出广泛的肌肉炎症。以往的研究证实了异草素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NLRP3 （nod样受体家族，pyrin结构域包含3）炎性体在异铁素缺乏的肌肉中被激活。然而，启动和延续免疫激活的分子机制尚不清楚。本研究计划的长期目标是了解dysferlin-deficient muscular dystrophy中肌肉炎症的分子机制，并探索靶向炎症信号通路治疗该疾病的治疗潜力。我们的初步研究发现，囊泡（特别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推测，从异常铁蛋白缺乏的肌肉中漏出的细胞内囊泡激活了NLRP3炎症小体，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囊泡的反应，操纵NLRP3炎性小体成分的表达以及体外和体内动物模型研究，显著推进对骨骼肌膜修复缺陷与免疫系统之间相互作用的理解。这些数据将开始确定炎症反应调节的潜在治疗靶点，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.