Immune and muscle cell interactions that modulate dystrophinopathy

点击翻译按钮获取中文摘要

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 the mdx mouse model of DMD to identify complex interactions between immune and muscle cells in muscular dystrophy and the consequences of these interactions on myofiber injury and regeneration. We specifically aim to test the hypothesis that macrophages in 4 week old mdx muscle are predominantly classically-activated and lyse mdx myotubes by free radical-mediated mechanisms (aim 1). In addition, we aim to test the hypothesis that macrophages in regenerative mdx muscle are alternatively-activated and promote muscle cell proliferation and differentiation (aim 2). Lastly, we will test the hypothesis that perturbations in the expression of Th1 and Th2 cytokines in vivo can significantly affect the course of mdx muscle injury and repair in vivo (aim 3). Elucidating the mechanisms that regulate that above interactions may result in the advancement of treatments that specifically perturb cytolytic immune cell interactions with muscle. To determine the physiological relevance of these macrophage phenotypes in vivo we propose using various mouse models. We will study the role of Th1 and Th2 cytokines in regulating the course of mdx muscle injury and repair by genetically ablating IL-10 and IFNg, which differentially regulate macrophage function. Because the interpretation of in vivo studies may be complicated by the numerous physiological factors that regulate macrophage functions, we will use n vitro assays to test the ability of classically- and alternatively-activated macrophages to promote muscle cell death and regeneration. The findings of this investigation may shed light on the inflammation-mediated, pathophysiological mechanisms that regulate dystrophinopathy.