Regulatory T cells in Duchenne muscular dystrophy

描述（由申请人提供）：杜氏肌营养不良症（DMD）是一种致命的肌肉萎缩疾病，由肌营养不良蛋白基因突变引起。目前DMD患者的治疗方案针对继发性疾病过程，如炎症，可加速疾病进展。然而，使用免疫抑制剂和合成代谢类固醇的治疗通常会导致长期使用的不良副作用。因此，研究旨在了解调节肌肉和免疫系统之间相互作用的细胞和分子机制是必要的。我们提出的研究可能有助于开发新的治疗方式，以减少副作用的炎症为目标。本文提出的研究的总体目标是使用DMD遗传小鼠模型来研究调节性T细胞（Tregs）在肌营养不良期间对肌纤维损伤和再生的作用。我们的具体目的是评估Tregs是否调节肌肉萎缩症的发生和进展（目的1）。此外，我们的目的是验证调节性T细胞通过促进巨噬细胞M2极化或直接调节肌肉再生来分泌促进肌肉修复因子的假设（目的2）。为了确定Tregs在体内的生理相关性，我们建议使用各种小鼠模型来检查Tregs在肌肉损伤，炎症和再生中的作用。具体来说，Treg耗竭和过继性转移试验的结合将被用来检查Treg在调节肌营养不良症过程中的作用。由于体内研究的解释可能会因许多调节肌肉再生的生理因素而变得复杂，我们将使用体外试验来测试Tregs直接调节肌肉再生的能力，使用测量肌肉细胞增殖和分化的试验。这项研究的结果可能会揭示炎症介导的病理生理机制，调节肌肉萎缩症的发展和进展。阐明treg在肌营养不良中的潜在作用以及treg介导的改善机制可能会导致特异性抑制细胞毒性免疫细胞与肌肉相互作用的治疗进展。

DESCRIPTION (provided by applicant): Duchenne muscular dystrophy (DMD) is a lethal, muscle-wasting disorder that is caused by mutations in the dystrophin gene. Current treatment options for DMD patients target secondary disease processes such as inflammation that can accelerate disease progression. However, therapies that employ immuno-suppressants and anabolic steroids commonly result in undesirable side effects with chronic use. Therefore, studies aimed at understanding the cellular and molecular mechanisms that regulate interactions between muscle and the immune system are needed. The investigation we propose may contribute to the development of new therapeutic modalities that target inflammation with reduced side effects. The overall objective of the investigation proposed here is to use genetic mouse models of DMD to examine the role of regulatory T cells (Tregs) on myofiber injury and regeneration during muscular dystrophy. We specifically aim to assess whether Tregs regulate the development and progression of muscular dystrophy (aim 1). In addition, we aim to test the hypothesis that regulatory T cells secrete factors that promote muscle repair by promoting M2 polarization of macrophages or directly modulating muscle regeneration (aim 2). To determine the physiological relevance of the Tregs in vivo we propose using various mouse models that will examine the role of Tregs on muscle injury, inflammation and regeneration. Specifically, a combination of Treg depletion and adoptive transfer assays will be employed to examine the role of Tregs in regulating the course of dystrophinopathy. Because the interpretation of in vivo studies may be complicated by the numerous physiological factors that regulate muscle regeneration, we will use in vitro assays to test the ability of Tregs to directly modulate muscle regeneration using assays that measure muscle cell proliferation and differentiation. The findings of this investigation may shed light on the inflammation-mediated, pathophysiological mechanisms that regulate the development and progression of muscular dystrophy. Elucidating the potential role of Tregs in muscular dystrophy and the mechanism of Treg-mediated amelioration in this setting may result in the advancement of treatments that specifically inhibit cytotoxic immune cell interactions with muscle.