Muscular Dystrophy Cooperative Research Center

描述(由申请者提供)：罗切斯特大学韦尔斯通MDCRC的主要优势是：5年来运营我们目前的韦尔斯通中心的经验；一大群积极进取的强直性肌营养不良(DM1)患者，他们渴望支持基础研究并参与临床研究；热情的研究人员，在DM1方面拥有长期的专业知识；以及包括NIH CTSA和最近资助的FSHD和神经肌肉研究的菲尔兹中心在内的培养环境。这些资产将使我们能够在未来继续我们目前的韦尔斯通中心科学项目，而不需要使用续订资金。我们的更新惠斯通中心将利用其资金用于2个科学项目和L科学资源核心，并专注于新的研究项目，以建立最佳方法来评估DM1患者的治疗效果，并确定潜在的新疗法。为了评估疾病进展的各个方面，项目1“强直性肌营养不良症的疾病进展”将进行：研究克隆细胞系中不稳定的DM1 CTG重复序列的躯体不稳定的潜在原因；在从80名患者队列中获得的细针肌肉活检标本中寻找突变的DM1 RNA的分子病理生理决定因素，每个患者提供腿部近端和远端肌肉的样本；还有一项纵向研究，通过对同一队列中80名患者在基线、12个月和36个月时的力量和功能、肌肉质量、肌强直和生活质量进行一系列测量，以确定疾病进展的最佳衡量标准(对患者具有临床意义)。为了确定潜在的新治疗方法，项目2“强直性肌营养不良症的实验治疗”将进行：在3个DM1小鼠模型上进行的肌肉盲基因治疗的试验；利用PTC Treeutics开发的筛选平台鉴定和鉴定显示肌肉盲转录后上调的小分子1；以及在2个DM1转基因小鼠模型上进行的治疗试验，使用完全由CAG重复序列组成的25个核苷酸的吗啡。科学资源核心结合了我们现有的组织资料库核心和NIH糖尿病患者及其家庭成员登记，为糖尿病研究提供国家资源。项目1和2对这一核心作出了贡献。培训/教育核心将在2-5年内培训1名博士后和1名博士后研究员，并将为患者、家庭成员、护理提供者和研究人员开发基于网络的教育材料。

DESCRIPTION (provided by applicant): Major strengths of the University of Rochester Wellstone MDCRC are: 5 years of experience in operating our current Wellstone Center; a large group of highly motivated patients with myotonic dystrophy (DM1) eager to support basic research and participate in clinical studies; enthusiastic investigators with longstanding expertise in DM1; and, a nurturing environment that includes a NIH CTSA and a recently funded Fields Center for FSHD and Neuromuscular Research. These assets will allow us to continue our current Wellstone Center scientific projects in the future without using renewal funds. Our renewal Wellstone Center will use its funds for 2 scientific projects and l scientific resources core and focus on new research projects to establish optimal methods to assess treatment efficacy in DM1 patients and to identify potential new therapies. To evaluate bench to bedside aspects of disease progression, Project 1, "Disease Progression in Myotonic Dystrophy", will undertake: studies of potential causes of somatic instability of the unstable DM1 CTG repeat in clonally derived cell lines; a search for molecular pathophysiologic determinants of mutant DM1 RNA in fine needle muscle biopsy specimens obtained from a cohort of 80 patients with each patient providing samples from a proximal and a distal leg muscle; and, a longitudinal study to identify optimal measures of disease progression (that are clinically significant to patients) by performing serial measurements of strength and function, muscle mass, myotonia, and quality of life in this same cohort of 80 patients at baseline, 12 and 36 months. To identify potential new treatments Project 2, "Experimental Therapy of Myotonic Dystrophy", will perform: a trial of muscle blind gene therapy in 3 mouse models of DM1; identification and characterization of small molecules showing post-transcriptional up-regulation of muscle blind 1 using the screening platform developed by PTC Therapeutics; and, a treatment trial in 2 transgenic mouse models of DM1 using a 25 nt morpholino composed entirely of CAG repeats. The scientific resources core combines our existing Tissue Repository Core and NIH Registry of DM Patients and Family members to provide national resources for research on DM. Projects 1 & 2 contribute to this core. The Training/Education core will train 1 pre- and 1 post-doctoral fellow during years 2-5 and will develop web based educational materials for patients, family members, care providers and researchers.