Five-Year NIH Grant for FSH Research

Friends of FSH Research, based in Kirkland, WA. is thrilled to announce that a $6.3 million, 5-year National Institutes of Health (N.I.H.) grant for FSH research has been awarded to the Seattle-based research consortium headed by Dr. Stephen Tapscott. This is one of the largest grants ever to be awarded for Facioscapulohumeral Muscular Dystrophy research.

The grant from the Neurological Disorders and Stroke division of the N.I.H. will fund this 5-year research project entitled "The Pathogenesis of FSHD." This grant will support the work of several researchers, in various laboratories around the world. The overall project is under the administration of Dr. Tapscott at the Fred Hutchinson Research Center in Seattle, Washington.

The NIH project funding, which began on April 15, will support four different projects in the collaborating laboratories.

Project 1: The genetic and epigenetic basis for FSHD, Silvere van der Maarel, Leiden University Medical Center, Leiden, The Netherlands

Project 2: RNA regulation in FSHD, Stephen Tapscott, Fred Hutchinson Cancer Research Center, Seattle, WA

Project 3: The role of CTCF in chromatin and nuclear organization at the FSHD locus, Galina Filippova, Fred Hutchinson Cancer Research Center, Seattle, WA

Project 4: FSH patient derived IPS cells to study the developmental regulation of DUX4 transcription, Dan Miller, University of Washington, Seattle, WA

This collaborative project will work in partnership with Dr. Rabi Tawil at the University of Rochester & utilize the resources of the Wellstone Center there.

Dr. Stephen Tapscott and Dr. Dan Miller were the second research team to receive funding from Friends of FSH Research for their pilot study "FSHMD Related Defects in Human Myogenesis" in 2006. They have continued to receive annual financial support from Friends of FSH Research over the past 4 years. We are extremely grateful to them for their dedication and we are delighted to have helped them earn this grant.

(study abstract)

Facioscapulohumeral muscular dystrophy (FSHD) Is one of the most common adult muscular dystrophies. Deletion of a subset of subtelomeric macrosatellite repeats (D4Z4 repeats) causes most cases of FSHD and results in a dominantly inherited disease. Recent work from our groups have shown a decrease of repressive epigenetic markings on the deleted allele, increased binding of regulatory factors to the deleted allele, and a complex set of coding and non-coding RNAs generated from the D4Z4 repeats. These findings strongly support a broad hypothesis for the pathophysiology of FSHD: loss of epigenetic silencing in the D4Z4 repeat leads to increased expression of an RNA species that causes the disease, either through an RNA or protein mediated mechanism. Our research groups will address specific and complementary aims that together will both test the broad hypothesis and identify the specific mechanism(s) of FSHD, which is critical for future therapy development. The aims of Project 1 (Dr. van der Maarel) will identify the DNA sequences and epigenetic changes specific to 4qA161 that are necessary to confer FSHD pathology. The aims of Project 2 (Dr. Tapscott) will determine whether the D4Z4-generated coding and non-coding RNAs have a role in FSHD pathology and identify mechanisms of generally suppressing transcription from the D4Z4 repeat region. The aims of Project 3 (Dr. Filippova) will be to determine whether CTCF binding on the disease associated allele regulates regional chromatin structure, RNA transcription, or nuclear localization. The aims of Project 4 (Dr. Miller) will be to use FSHD-derived IPS cells to identify the transcriptional an epigenetic determinants of FSHD, and the regulatory regions in the D4Z4 region. Dr. Tawil (Core A) has established an FSHD Bioresources Core with uniformly collected and well-characterized biological samples from FSHD and control individuals. The aims of Core A will be to collect DNA from blood samples for genetic analysis, fibroblast and myoblasts from skin and muscle for biological studies, and muscle biopsies for histochemical and in situ biological analyses. The Administrative Core (Core B) will coordinate the administration of the grant, communications among the participants, and reporting responsibilities. Together, these studies combine genetic, epigenetic, transcriptional and developmental approaches to defining the molecular deficits that cause FSHD and will provide a new basis for developing therapies.

Funding provided by the National Institute of Neurological Disorders and Stroke division of the National Institutes of Health.