The pathogenesis of facioscapulohumeral muscular dystrophy

面肩肱型肌营养不良症的发病机制

• 批准号: 9767865
• 负责人: Stephen J Tapscott
• 金额: $ 119.72万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2021-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767865
• 关键词: Address; Affect; Biocompatible Materials; Biological; Biological Markers; Cells; Chromatin Remodeling Factor; 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; Pathologic; 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; clinical phenotype; derepression; genetic variant; genome-wide; novel; preclinical development; preclinical study; programs; public health relevance; targeted treatment; therapeutic development; translational study

 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（由申请方提供）：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伴随的治疗开发新机会。主要项目包括：项目1，抑制D4Z4重复的途径和机制（Silvere货车der Maarel），将确定重复元件抑制的分子机制。项目2，FSHD中的重复去阻遏和RNA介导的毒性（Robert布拉德利），将确定与基因组中重复元件的去阻遏相关的分子后果和RNA毒性。项目3，靶向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的机制，作为FSHD的治疗方法。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，并通过开发结果指标（包括生物标志物和患者评估）为临床试验做准备。行政核心（Stephen Tapscott）将协调研究者之间的活动和沟通，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将共同解决重复介导的沉默途径中表观遗传沉默D4Z4的机制和途径，确定重复RNA无效沉默和异常RNA积累的病理生理后果，为治疗开发开拓新的机会，并为临床试验研究提供必要的资源。

项目成果

The RNA Surveillance Factor UPF1 Represses Myogenesis via Its E3 Ubiquitin Ligase Activity.

• DOI: 10.1016/j.molcel.2017.05.034
• 发表时间: 2017-07-20
• 期刊: Molecular cell
• 影响因子: 16
• 作者: Feng Q;Jagannathan S;Bradley RK
• 通讯作者: Bradley RK

Relationship of DUX4 and target gene expression in FSHD myocytes.

• DOI: 10.1002/humu.24171
• 发表时间: 2021-04
• 期刊: Human mutation
• 影响因子: 3.9
• 作者: Chau J;Kong X;Viet Nguyen N;Williams K;Ball M;Tawil R;Kiyono T;Mortazavi A;Yokomori K
• 通讯作者: Yokomori K

Congenital myotonic dystrophy-an RNA-mediated disease across a developmental continuum.

• DOI: 10.1101/gad.302893.117
• 发表时间: 2017-06-01
• 期刊: Genes & development
• 影响因子: 10.5
• 作者: Jagannathan S;Bradley RK
• 通讯作者: Bradley RK

Scapular dyskinesis in myotonic dystrophy type 1: clinical characteristics and genetic investigations.

强直性肌营养不良 1 型肩胛运动障碍：临床特征和遗传研究。

• DOI: 10.1007/s00415-019-09494-8
• 发表时间: 2019
• 期刊: Journal of neurology
• 影响因子: 6
• 作者: Voermans,NC;vanderBilt,RC;IJspeert,J;Hogrel,JY;Jeanpierre,M;Behin,A;Laforet,P;Stojkovic,T;vanEngelen,BG;Padberg,GW;Sacconi,S;Lemmers,RJLF;vanderMaarel,SM;Eymard,B;Bassez,G
• 通讯作者: Bassez,G

A unifying genetic model for facioscapulohumeral muscular dystrophy.

• DOI: 10.1126/science.1189044
• 发表时间: 2010-09-24
• 期刊: Science (New York, N.Y.)
• 作者: Lemmers RJ;van der Vliet PJ;Klooster R;Sacconi S;Camaño P;Dauwerse JG;Snider L;Straasheijm KR;van Ommen GJ;Padberg GW;Miller DG;Tapscott SJ;Tawil R;Frants RR;van der Maarel SM
• 通讯作者: van der Maarel SM