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.
FSHD is one of the most common forms of muscular dystrophy and yet the basic pathophysiology resulting in muscle weakness in the disorder is unknown. The proposed studies of FSHD disease biomarkers and disease modifiers undertake to reveal the underlying mechanisms responsible for the pathophyisiology of FSHD and to develop disease models for preclinical studies to develop FSHD therapeutics.
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