Project 4: Model Studies for FSHD Biomarkers. Though genetic changes underlying facioscapulohumeral muscular dystrophy (FSHD) have been identified, there is a need to identify downstream pathogenetic mechanisms and to find additional disease biomarkers. Accordingly, the studies under Project 4 will focus on the use of potential mouse models and cultured human FSHD muscle cells to (i) discover or validate FSHD biomarkers, (ii) identify downstream pathogenetic mechanisms, and (iii) test possible therapies. Because affected FSHD muscles show only a small amount of regeneration and repair, it is possible that FSHD pathology could be ameliorated if regeneration and/or muscle hypertrophy were increased. One set of experiments, therefore, will determine if such treatments decrease biomarkers of disease in potential FSHD mouse models. Also, there is considerable indirect evidence to support the idea that apoptosis contributes to FSHD pathogenesis, e.g., activated caspase-3 is found in human FSHD muscle fibers and human FSHD myogenic cells appear to be more susceptible to cell death. No studies have yet directly assessed the contribution of apoptosis to FSHD pathogenesis, and the mechanisms of muscle cell apoptosis are not fully understood. The additional sets of studies are designed to provide a direct assessment of the role of apoptosis in FSHD, to investigate signs of apoptosis as disease biomarkers, and to elucidate apoptotic pathways in diseased muscle cells.
The Specific Aims of Project 4 are to: (1) Determine in FSHD mouse models if apoptosis contributes to pathogenesis and if signs of apoptosis are valid disease biomarkers;(2) Determine if treatments that improve regeneration and/or induce hypertrophy will decrease disease biomarkers in FSHD models;and (3) Elucidate mechanisms underlying the increased susceptibility of human FSHD myoblasts and myotubes to cell death upon oxidative stress. Relevance to Public Health. The studies will increase our knowledge of biomarkers for disease progression and how genetic changes lead to disease in FSHD. The experiments could also identify possible new methods to ameliorate FSHD.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HD060848-05
Application #
8380043
Study Section
Special Emphasis Panel (ZAR1-KM-J)
Project Start
Project End
2013-03-01
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
5
Fiscal Year
2012
Total Cost
$249,610
Indirect Cost
$63,796
Name
Boston Biomedical Research Institute
Department
Type
DUNS #
058893371
City
Watertown
State
MA
Country
United States
Zip Code
02472
Chagarlamudi, Hema; Corbett, Alastair; Stoll, Marion et al. (2017) Bone health in facioscapulohumeral muscular dystrophy: A cross-sectional study. Muscle Nerve 56:1108-1113
Shaw, Natalie D; Brand, Harrison; Kupchinsky, Zachary A et al. (2017) SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome. Nat Genet 49:238-248
Ansseau, Eugénie; Vanderplanck, Céline; Wauters, Armelle et al. (2017) Antisense Oligonucleotides Used to Target the DUX4 mRNA as Therapeutic Approaches in FaciosScapuloHumeral Muscular Dystrophy (FSHD). Genes (Basel) 8:
Eichinger, Katy; Heatwole, Chad; Heininger, Susanne et al. (2017) Validity of the 6 minute walk test in facioscapulohumeral muscular dystrophy. Muscle Nerve 55:333-337
Widrick, Jeffrey J; Alexander, Matthew S; Sanchez, Benjamin et al. (2016) Muscle dysfunction in a zebrafish model of Duchenne muscular dystrophy. Physiol Genomics 48:850-860
Chen, Jennifer Cj; King, Oliver D; Zhang, Yuanfan et al. (2016) Morpholino-mediated Knockdown of DUX4 Toward Facioscapulohumeral Muscular Dystrophy Therapeutics. Mol Ther 24:1405-11
Ansseau, Eugénie; Eidahl, Jocelyn O; Lancelot, Céline et al. (2016) Homologous Transcription Factors DUX4 and DUX4c Associate with Cytoplasmic Proteins during Muscle Differentiation. PLoS One 11:e0146893
Sakellariou, Paraskevi; O'Neill, Andrea; Mueller, Amber L et al. (2016) Neuromuscular electrical stimulation promotes development in mice of mature human muscle from immortalized human myoblasts. Skelet Muscle 6:4
Choudhury, Sourav R; Fitzpatrick, Zachary; Harris, Anne F et al. (2016) In Vivo Selection Yields AAV-B1 Capsid for Central Nervous System and Muscle Gene Therapy. Mol Ther 24:1247-57
Eidahl, Jocelyn O; Giesige, Carlee R; Domire, Jacqueline S et al. (2016) Mouse Dux is myotoxic and shares partial functional homology with its human paralog DUX4. Hum Mol Genet 25:4577-4589

Showing the most recent 10 out of 32 publications