Paul D. Wellstone Muscular Dystrophy Cooperative Research Center

罗彻斯特大学韦尔斯通医学中心的主要优势是：10年的韦尔斯通中心运营经验；一大群高度积极的肌强直性营养不良（DM1）患者渴望支持转化研究并参与临床研究；长期从事临床研究的热心研究者；合作者分享了我们的紧急承诺，即确定和验证可靠的终点和生物标志物，为DM1的治疗试验做准备；一个培育环境，包括NIH CTSI网络和DM1社区主要利益相关者的支持。这些资产将允许神经肌肉临床试验网络成为试验准备，并允许进一步探索RNA毒性（剪接病）作为疾病病理机制和生物标志物。我们的更新Wellstone中心将支持2个科学项目和1个科学资源核心，并寻求验证我们当前Wellstone研究中确定的有前景的临床终点测量和骨骼肌剪接改变。我们更新的项目1包括一项多中心验证研究，以确认有希望的终点测量的有效性，并将评估小针肌肉活检剪接测定作为有用的生物标志物的可行性和可靠性。100名DM1患者将在0个月和12个月时接受相同的临床评估来回答这些问题。一个更大的400名DM1患者队列将接受临床检查，以评估疾病严重程度，并提供血液用于DMPK CTG重复序列大小和MBNL1和其他位点的遗传变异的DNA分析。我们目前的肌肉活检数据表明，组织中CTG重复大小不能预测肌肉无力的严重程度，这表明其他遗传因素可能影响DM1。项目2将在转基因糖尿病小鼠模型中检测反义药物对心功能的治疗作用。科学核心包含糖尿病患者和家庭成员的国家注册和存储库。它支持项目1和项目2。培训/教育核心培养1名博士预科生和1名博士后，并提供教材。

DESCRIPTION (provided by applicant): Major Strengths of the University of Rochester Wellstone MDCRC are: 10 years of experience in operating our current Wellstone Center; a large group of highly motivated patients with myotonic dystrophy (DM1) eager to support translational research and participate in clinical studies; enthusiastic investigators with longstanding expertise in clinical studies; collaborators sharing our urgent commitment to identify and validate reliable endpoints and biomarkers to prepare for treatment trials in DM1; and a nurturing environment that includes a NIH CTSI network and support from major stakeholders in the DM1 community. These assets will allow a network of neuromuscular clinical trialists to become trial ready and permit further exploration of RNA toxicity (spliceopathy) as a disease pathomechanism and biomarker. Our renewal Wellstone Center will support 2 scientific projects and 1 scientific resources core and seeks to validate promising clinical endpoint measures and skeletal muscle splicing alterations identified in our current Wellstone study. Project 1 in our renewal includes a multicenter validation study to confirm the usefulness of promising endpoint measures and will evaluate feasibility and reliability of small needle muscle biopsy splicing assays as a useful biomarker. A cohort of 100 DM1 patients will undergo identical clinical evaluations at 0 and 12 months to answer these questions. A larger cohort of 400 DM1 patients will undergo clinical exams to assess disease severity and provide blood for DNA analysis of DMPK CTG repeat size and genetic variants at MBNL1 and other loci. Our current muscle biopsy data indicate CTG repeat size in tissue does not predict the severity of muscle weakness, suggesting that other genetic factors may influence DM1. Project 2 will examine therapeutic effects of antisense drugs on cardiac function in transgenic mouse models of DM. The Scientific Core contains the National Registry of DM Patients and Family Members and Repository. It supports Projects 1 and 2. The Training/Education Core trains 1 pre-doctoral and 1 post-doctoral fellow and will provide educational materials.