The pathogenesis of facioscapulohumeral muscular dystrophy

面肩肱型肌营养不良症的发病机制

基本信息

批准号：
8998512
负责人：
Stephen J Tapscott
金额：
$ 129.87万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2020-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8998512
关键词：
Address Affect Biocompatible Materials Biological Biological Markers Cells Chromatin Chromatin Structure Clinical Clinical Trials Communication Consensus D4Z4 Development Disease Elements Enhancers Epigenetic Process Facioscapulohumeral Muscular Dystrophy Family Funding Future Genes Genetic Transcription Genetic Variation Genome Health Human Individual Mediating Modeling Molecular Mutate Mutation Office of Administrative Management Oligonucleotides Outcome Measure Pathogenesis Pathway interactions Patients Penetrance Peptides Pharmaceutical Preparations Proteins RNA Repetitive Sequence Repression Research Research Activity Research Personnel Research Project Grants Resources Skeletal Muscle Somatic Cell Testing Therapeutic Clinical Trial Therapeutic Intervention Toxic effect Transcriptional Silencer Elements Translating Validation base clinical phenotype derepression genetic variant genome-wide meetings novel pre-clinical preclinical study programs public health relevance therapeutic development

项目摘要

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.

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开发新机遇：项目 1，抑制 D4Z4 重复的途径和机制。（Silvere van der Maarel）将确定 FSHD 中重复元件抑制的分子机制，即重复去抑制和 RNA 介导的毒性（Robert Bradley）。与基因组中重复元件去抑制相关的分子后果和 RNA 毒性项目 3，以 D4Z4 序列为目标来增强重复抑制（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。生物资源核心是 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，并通过制定结果指标（包括生物标志物和患者评估）为临床试验做好准备。行政核心（Stephen Tapscott）将协调研究人员之间的活动和沟通，提供预算和行政监督，并协调外部顾问委员会提供的科学成果，这三个项目和两个核心将共同解决表观遗传学的机制和途径。沉默重复介导的沉默途径中的 D4Z4，确定重复 RNA 低效沉默和异常 RNA 积累的病理生理后果，探索治疗开发的新机会，并提供必要的资源将研究转向临床试验。