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.

Public Health Relevance

The significance of the combined Projects and Cores is that it will determine whether repeat-mediated epigenetic silencing and repetitive element expression represent specific pathways that can be targeted for therapeutic intervention in FSHD. The health relatedness of the proposal is that it will provide the basis for clinical therapeutic trial in FHSD.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Nuckolls, Glen H
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Fred Hutchinson Cancer Research Center
United States
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Lim, Jong-Won; Wong, Chao-Jen; Yao, Zizhen et al. (2018) Small noncoding RNAs in FSHD2 muscle cells reveal both DUX4- and SMCHD1-specific signatures. Hum Mol Genet :
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