The UMMS Wellstone is pursuing three collaborative and complementary research projects with the overriding theme of “Biomarkers for Therapeutics of FSHD”.
The severity of FSHD is variable among individuals, even within the same family with the same contracted D4Z4 allele and permissive haplotype. These findings implicate a role for additional genetic determinants of FSHD disease that modulate its clinical manifestations and severity. The overall goal of Project 1 is to recruit families with individuals divergent for FSHD clinical symptoms for exome and genome sequencing analyses to identify genetic modifiers of disease severity in families with genetic carriers of FSHD.
Molecular biomarkers of FSHD disease pathology: Molecular technologies are utilized to identify FSHD disease biomarkers in the FSHD transcriptome to reveal underlying mechanisms of FSHD muscle pathology and to effectively and efficiently monitor efficacy of FSHD drugs in clinical trials.
Epigenetic biomarkers of FSHD disease severity: Epigenetic mechanisms have a central role in FSHD disease pathology and progression. Studies focus on mechanisms that regulate the DNA methylation status of the 4q35 locus, to modify expression of the FSHD disease gene, DUX4, in families of genetic carriers of 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 largely unknown. The goal of Project 3 is to develop novel animal models of FSHD, including humanized mouse muscle xenograft models and zebrafish models, for two purposes. These models will 1) enable studies of the pathogenesis of FSHD, as well as 2) serve as platforms for preclinical studies to develop FSHD therapeutics.