The pathogenesis of facioscapulohumeral muscular dystrophy

 描述(由申请人提供)：PPG的总体主题将是确定与重复元件去抑制相关的病理机制以及随之而来的治疗发展的新机会。主要项目将是：项目1，抑制D4Z4重复的途径和机制(Silvere Van Der Maarel)，将确定重复元件抑制的分子机制。项目2，FSHD中的重复去抑制和RNA介导的毒性(Robert Bradley)，将确定与基因组中重复元件的去抑制相关的分子后果和RNA毒性。项目3，针对D4Z4序列以增强重复抑制(Stephen Tapscott)，将确定增强重复介导的表观遗传抑制作为FSHD治疗的机制。生物资源核心，FSHD研究和临床试验的资源(Rabi Tawil)，将为每个项目提供必要的生物资源，并通过制定结果衡量标准，包括生物标记物和患者评估，为临床试验做准备。行政核心(史蒂芬·塔普斯科特)将协调调查人员之间的活动和沟通，提供预算和行政监督，并协调外部咨询委员会提供的科学监督。这三个项目和两个核心一起将解决在重复介导的沉默途径中汇聚到表观遗传学沉默D4Z4的机制和途径，确定重复RNA的低效沉默和变异RNA积累的病理生理后果，为治疗开发开拓新的机会，并为将研究推向临床试验提供必要的资源。

 DESCRIPTION (provided by applicant): The overall theme of the PPG will be identifying the pathological mechanisms associated with repetitive element de-repression and the concomitant new opportunities for therapeutic development. The major projects will be: Project 1, pathways and mechanisms repressing D4Z4 repeats (Silvere van der Maarel), will identify the molecular mechanisms of repeat element repression. Project 2, repeat derepression and RNA-mediated toxicity in FSHD (Robert Bradley), will determine the molecular consequences and RNA-toxicity associated with de-repression of repetitive elements in the genome. Project 3, targeting the D4Z4 sequence to enhance repeat repression (Stephen Tapscott), will identify mechanisms of enhancing repeat-mediated epigenetic repression as a therapy for FSHD. The Bioresources Core, resources for FSHD research and clinical trials (Rabi Tawil), will provide biological resources necessary for each project and to prepare for clinical trials through development of outcomes measures, including biomarkers and patient assessments. The Administrative Core (Stephen Tapscott) will coordinate the activities and communications among the investigators and provide budgetary and administrative oversight, and coordinate the scientific oversight provided by the External Advisory Board. Together these three Projects and two Cores will address the mechanisms and pathways that converge to epigenetically silence D4Z4 in the repeat-mediated silencing pathways, determine the pathophysiologic consequences of inefficient silencing of repetitive RNAs and accumulation of aberrant RNAs, exploit new opportunities for therapeutic development, and provide the resources necessary for moving studies toward clinical trials.