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

描述（由申请人提供）：本MDCRC围绕以下概念组织：限制肌营养不良症中的纤维化将有助于通过患者自身的卫星细胞修复延长成功再生的时间，增加与增加患者肌肉修复能力的治疗相关的益处，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，本MDCRC的主要目的是促进实现临床上有用的抑制纤维化的药理学方法，并确定现有的最佳纤维化药理学抑制剂，以及推动新型抑制剂的开发。我们的进一步目标是开发非侵入性成像技术，以评估骨骼肌和心肌纤维脂肪替代的进展。 在项目1中，Sweeney和Spencer博士（与McNally、巴顿、Miceli、Discher和Epstein博士合作）将跟踪mdx和A/J小鼠疾病进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小鼠疾病病理学的影响。在项目2中，McNally博士将通过检查不同遗传背景的肌营养不良症小鼠模型来寻找心脏纤维化的修饰剂。斯坦纳尔逊（加州大学洛杉矶分校）将合作项目2。在项目3中，Walter和Vandenborne博士将继续他们的项目，重点是开发肌营养不良症疾病进展的非侵入性监测。他们将在这方面得到Bonnemann博士、Finkel博士、McNally博士、Sweeney博士和Byrne博士的帮助和建议。一个行政核心（核心A）将支持所有项目，以及为我们的专题讨论会和两年一度的国际肌营养不良症会议提供行政支持，并监督该中心非NIH资金的使用。该中心还将有一个主要的培训和教育部分，在奥斯塔普博士和芬克尔博士的指导下（核心B：培训和教育核心）。生理学评估核心（核心C）将支持项目1，并继续作为评价肌营养不良小鼠模型治疗效果的国家来源。

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.