Failed Regeneration in the Muscular Dystrophies: Inflammation, Fibrosis and Fat

描述(申请人提供)：MDCRC是围绕这样一个概念组织的，即限制肌肉营养不良的纤维化将有助于通过患者自己的卫星细胞修复来延长成功的再生期，增加与提高患者肌肉修复能力的治疗相关的好处，并将延长患者可以从最终的病毒基因或干细胞治疗中受益的年龄。因此，MDCRC的主要目标是促进临床上有用的抑制纤维化的药理学手段的实现，并确定现有的最好的纤维化药理抑制剂，以及推动新类别抑制剂的开发。我们的进一步目标是开发非侵入性成像技术来评估骨骼肌和心肌纤维脂肪替代的进展。 在项目1中，Sweeney博士和Spencer博士(与McNally、Barton、Miceli、Discher和Epstein博士合作)将跟踪MDX和A/J小鼠疾病发展过程中卫星细胞的命运，同时表征肌肉组织、纤维化和脂肪的变化。该项目将继续分析炎症和/或纤维化的抑制剂及其对MDX和A/J小鼠疾病病理的影响。在项目2中，麦克纳利博士将通过研究不同遗传背景下的肌营养不良症小鼠模型来寻找心脏纤维化的修饰物。Stan Nelson(加州大学洛杉矶分校)将在项目2上合作。在项目3中，Walter博士和Vandenborne博士将继续他们的项目，重点是开发对肌营养不良症疾病进展的非侵入性监测。在这一努力中，他们将得到Bonnemann、Finkel、McNally、Sweeney和Byrne博士的帮助和建议。行政核心(核心A)将支持所有项目，并为我们的研讨会和每两年举行一次的国际肌营养不良症会议提供行政支持，并监督中心非NIH资金的使用。该中心还将有一个主要的培训和教育部分，由奥斯塔普博士和芬克尔博士(核心B：培训和教育核心)领导。生理评估核心(核心C)将支持项目1，并继续作为评估肌营养不良症小鼠模型的治疗措施的全国性来源。

DESCRIPTION (provided by applicant): This MDCRC is organized around the concept that limiting fibrosis in the muscular dystrophies will help extend the period of successful regeneration via the patients' own satellite cell repair, increase the benefits associated with therapies that increase the patients' muscle repair capacity, and will extend the age at which patients can benefit from eventual viral gene or stem cell therapies. Thus the primary objectives of this MDCRC are to facilitate the attainment of clinically useful pharmacological means of inhibiting fibrosis and to identify the best existing pharmacological inhibitors of fibrosis, as well as drive the development of new classes of inhibitors. Our further goal is to develop non-invasive imaging techniques to assess the progression of fibro-fatty replacement of skeletal and cardiac muscles. In Project 1, Drs. Sweeney and Spencer (in collaboration with Drs. McNally, Barton, Miceli, Discher and Epstein) will follow the fate of satellite cells during the progression of disease in mdx and A/J mice, while characterizing changes in muscular tissue, fibrosis and fat. The project will go on to analyze inhibitors of inflammation and/or fibrosis and their impact on disease pathology in mdx and A/J mice. In Project 2, Dr. McNally will search for modifiers of cardiac fibrosis by examining mouse models of muscular dystrophy on different genetic backgrounds. Stan Nelson (UCLA) will collaborate on Project 2. In Project 3, Drs. Walter and Vandenborne will continue their project focused on the development of non-invasive monitoring of disease progression in muscular dystrophy. They will be aided and advised in this effort by Drs. Bonnemann, Finkel, McNally, Sweeney and Byrne. An Administrative Core (Core A) will support all projects, as well as provide the administrative support for our symposia and bi-annual international muscular dystrophy meeting, and to oversee the use of non-NIH funding for the Center. The Center will also have a major training and educational component, under the direction of Drs. Ostap and Finkel (Core B: Training and Education Core). A Physiological Assessment Core (Core C) will support Project 1 and continue as a national source for evaluating therapeutic inten/entions in mouse models of Muscular Dystrophy.