Biomarkers for Therapy of FSHD (U54)

描述(由申请人提供)：我们的U54 Wellstone MD CRC的首要目标是追求基于生物标记物的研究策略，这将促进我们对FSHD肌肉无力的潜在病理生理学的理解，并使治疗FSHD的动物模型和治疗技术的发展成为可能。我们研究的中心是来自FSHD家族的大量有文件记录的生物材料，使得对FSHD潜在的分子病理生理学和导致这种疾病临床变异性的疾病修饰物的统计动力研究成为可能。这个生物资料库将扩大到包括来自有和没有家族病史的个人的血液、肌肉和衍生的肌肉祖细胞，以及典型受影响的一级亲属和没有FSHD等位基因的对照，作为全球FSHD研究人员和三个相互关联、合作的中心项目的资源。中心项目将利用最新的AT基因组测序、深度测序RNAseq和DNA甲基化技术来确定遗传和表观遗传修饰因素，并确定与FSHD疾病病理和进展相关的疾病生物标记物。FSHD的新型人源化小鼠和斑马鱼模型将被利用来更好地了解FSHD疾病的病理，并开发疾病特异性治疗方法，包括基因治疗和吗啡治疗。该中心的项目将由一个由7名互动研究人员及其合作者组成的重组小组进行，他们在临床医学、遗传学、分子和细胞生物学以及计算生物学和基因组学方面具有互补的专业知识。教育和培训核心将提供FSHD临床和基础研究方面的实践研究经验。行政核心将与我们的主要患者倡导团体FSH协会合作，定期组织WebX会议数据共享会议、FSHD研讨会、患者-研究人员联网会议，以及中心调查人员、实习生、NIH和中心咨询委员会的年度务虚会，以审查当前的进展并制定FSHD治疗的新方向。

DESCRIPTION (provided by applicant): The overarching goal of our U54 Wellstone MD CRC is to pursue a biomarker-based research strategy that will further our understanding of the underlying pathophysiology of FSHD muscle weakness and enable development of animal models and therapeutic technologies for treatment of FSHD. Central to our research is a large repository of well-documented biomaterials from FSHD families, making possible statistically powered studies of the underlying molecular pathophysiology of FSHD and disease modifiers responsible for the clinical variability of this disease. This biorepository will be expanded to include blood, muscle and derived muscle progenitor cells from individuals with and without family history of disease along with 1st degree relatives who are classically affected and those without the FSHD allele as controls, to serve as resource for FSHD researchers worldwide and for three inter-related, collaborative Center projects. Center projects will utilize-state-of-the at genome sequencing, deep sequencing RNAseq and DNA methylation technologies to identify genetic and epigenetic modifiers and to identify disease biomarkers related to FSHD disease pathology and progression. Novel humanized mice and zebrafish models of FSHD will be exploited to better understand FSHD disease pathology and to develop disease specific therapies including gene and morpholino therapies. Center projects will be pursued by a reorganized group of 7 interactive investigators and their collaborators with complementary expertise in clinical medicine, genetics, molecular and cellular biology, and computational biology and genomics. An Educational and Training Core will provide hands-on research experience in FSHD clinical and basic research. An Administrative Core will partner with our primary patient advocacy group, the FSH Society, to organize regular WebX conferencing data-sharing meetings, FSHD workshops, patient-researcher networking meetings, and an annual retreat for Center investigators, trainees, NIH and the Center Advisory Committee to review current progress and develop new directions towards therapeutics for FSHD.