Wellstone Muscular Dystrophy Center: Children's Nat'l Med Ctr

描述（由申请人提供）：杜氏肌营养不良症是最常见和破坏性的肌营养不良症。迄今为止，唯一有效的治疗方法是长期使用皮质类固醇，但患者对治疗的反应不佳，这种益处的基础尚不清楚。该中心申请的主题是增加我们对杜氏肌营养不良症的病理生理学的理解，在多个互补但相互作用的水平。拟议的研究项目建议将复杂的疾病病理生理学分解为组成生物化学途径，其中每一个都显示出串扰的证据。这种交叉对话的途径导致项目和专业知识的协同作用，在拟议的中心。项目1建议研究杜氏营养不良的遗传修饰剂，利用广泛的患者资源，通过国际神经肌肉研究合作组（CINRG）。这是该中心的“临床项目”。项目2研究细胞损伤和重塑途径。年龄和疾病进展的功能在人类患者中，在转基因小鼠中测试的病理生理模型。项目3研究mdx小鼠模型中随年龄变化的卫星细胞特征和激活问题。拟议的中心集中在遗传医学研究中心，这是一个由70名科学家组成的跨学科小组，主要关注临床，临床试验，分子生物学和伦理学等各个层面的肌营养不良症。这三个拟议的项目由三个核心支持：行政核心，人类临床核心（CINRG）和生物信息学和计算核心。本中心的申请已进行了广泛的修订，以回应以前的批评，包括新发表的手稿，解决有关可行性的技术问题。拟建中心的主要人员（霍夫曼博士、Escolar博士、Pardaran博士、Chen博士、Nagaraju博士、Pegoraro博士、Leshner博士）继续保持着在神经肌肉疾病和提案主题方面的良好出版记录，在过去5年中共发表了129篇论文，其中18篇由两名或两名以上的主要人员共同撰写。]

Description (provided by applicant):Duchenne muscular dystrophy is the most common and devastating of the muscular dystrophies. The only effective therapy to date is chronic use of corticosteroids, yet patients respond variably to treatment and the basis of this benefit is not understood. The theme of the proposed Center application is to increase our understanding of the pathophysiology of Duchenne muscular dystrophy at multiple complementary yet interacting levels. The proposed research projects propose to break down the complex disease pathophysiology into component biochemical pathways, each of which shows evidence of cross-talk. This cross-talk in pathways leads to a synergism of projects and expertise in the proposed Center. Project 1 proposes to study genetic modifiers of Duchenne dystrophy, taking advantage of extensive patient resources available through the Cooperative International Neuromuscular Research Group (CINRG). This is the "clinical project" for the Center. Project 2 studies cell damage and remodeling pathways as. a function of age and disease progression in human patients, with pathophysiological models tested in transgenic mice. Project 3 studies the issues of satellite cell characterization and activation as a function of age in the mdx mouse model. The proposed Center is centered in the Research Center for Genetic Medicine, a interdisciplinary group of -70 scientists with a major focus on the muscular dystrophies at all levels from clinics, clinical trials, molecular biology, and ethics. The three proposed projects are supported by three Cores; an Administrative Core, a Human Clinical Core (CINRG), and a Bioinformatics and Computing Core. This Center application has been extensively revised to respond to the previous critiques, including new published manuscripts addressing technical concerns regarding feasibility. The key personnel of the proposed Center (Drs. Hoffman, Escolar, Partridge, Chen, Nagaraju, Pegoraro, Leshner) have continued their strong publication record in neuromuscular disease and the topics of the proposal, with 129 manuscripts over the last 5 years, including 18 co-authored by two or more key personnel. ]