Regulatory T cells in Duchenne muscular dystrophy

杜氏肌营养不良症中的调节性 T 细胞

基本信息

批准号：
8704711
负责人：
Sergio Armando Villalta
金额：
$ 5.89万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8704711
关键词：
Acute Address Adoptive Transfer Adverse effects Anabolic steroids Autoantigens Binding Biological Assay Cell Communication Cell Differentiation process Cell Proliferation Cells Cessation of life Chronic Clinical Research Communities Complex Data Development Disease Disease Progression Duchenne muscular dystrophy Dystrophin Environment Frequencies Genes Genetic Immune Immune response Immune system Immunity Inflammation Inflammatory Response Injury Interleukin-10 Investigation Life Light Macrophage Activation Measures Mediating Modality Molecular Muscle Muscle Cells Muscular Dystrophies Mutation Natural regeneration Necrosis Outcome Pathway interactions Patients Physiological Population Process Proteins Reaction Regulatory T-Lymphocyte Relaxin Research Design Research Personnel Role Series Source Staging Testing Therapeutic Viral base cytokine cytotoxic efficacy testing gene therapy in vitro Assay in vivo injured injury and repair macrophage mouse model muscle degeneration muscle regeneration novel novel therapeutics prevent public health relevance relaxin receptor repaired tissue repair wasting

项目摘要

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.

描述（由申请人提供）：Duchenne肌肉营养不良（DMD）是一种致命的，浪费肌肉的疾病，是由肌营养不良蛋白基因突变引起的。 DMD患者的当前治疗方案针对的是继发性疾病过程，例如炎症，可以加速疾病进展。但是，采用免疫抑制剂和合成代谢类固醇的疗法通常会导致长期使用的不良副作用。因此，需要研究旨在了解调节肌肉与免疫系统之间相互作用的细胞和分子机制。我们提出的调查可能有助于发展新的治疗方式，这些方法靶向炎症，副作用减少。这里提出的研究的总体目标是使用DMD的遗传小鼠模型来检查调节性T细胞（Tregs）对肌营养不良过程中肌纤维损伤和再生的作用。我们特别旨在评估Treg是否调节肌肉营养不良的发展和进展（AIM 1）。此外，我们旨在检验以下假设：调节性T细胞通过促进巨噬细胞的M2极化或直接调节肌肉再生来促进肌肉修复的因素（AIM 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，这些模型将检查Tregs对肌肉损伤，炎症和再生的作用。具体而言，将采用Treg耗竭和收养转移测定法的组合来检查Treg在调节肌营养不良过程中的作用。由于对体内研究的解释可能会因调节肌肉再生的众多生理因素而变得复杂，因此我们将使用体外测定法测试Treg使用测量肌肉细胞增殖和分化的测定法直接调节肌肉再生的能力。这项研究的发现可能会阐明炎症介导的病理生理机制，这些机制调节了肌肉营养不良的发育和进展。阐明Treg在肌肉营养不良中的潜在作用以及在这种情况下Treg介导的改善的机理可能会导致治疗的发展，这些治疗方案专门抑制了细胞毒性免疫细胞与肌肉的相互作用。