FSHD is one of the more common forms of muscular dystrophy in humans with a very unusual and poorly understood biochemical, developmental and molecular underpinning. What is clear is that the D4Z4 repeat deletion in some way influences the expression of genes in muscle in a dominant fashion to cause a variable degree of myofiber degeneration and muscle weakness in different patients. We have established by both proteomic and RNA profiling of muscle biopsies from FSHD patient that both proteins and RNA change expression patterns in diseased tissue. In addition, we have observed in 5 FSHD families from Brazil that some asymptomatic carriers of D4Z4 deletions substantially increase expression of 12 genes including 2 chemokines encoded on chromosome 4 which are only modestly changed in symptomatic patients. We propose to follow up on these findings and use protein, microRNA and mRNA expression profiling as an approach to understanding the differences in disease severity in different individuals with the D4Z4 deletion with the hope that this understanding might lead to the discovery of biomarkers which will be useful in evaluating potential treatments of FSHD. We propose to accomplish this goal according to the following specific aims: 1) Continue to profile mRNA from FSHD patients, control muscle and cell lines generated from differentially affected muscles and confirm existing and new array data by RT-PCR. 2) Confirm our observation on the differential expression of certain miRNAs in FSHD muscle and look at the change in expression of the predicted targets of our observed miRNAs in the mRNA expression arrays from aim 1. We will also ablate these candidate miRNAs in myogenic cell lines to see if we can recapitulate in culture the gene expression changes we see in skeletal muscle of FSHD patients. 3) Lastly, we will continue parallel experiments to define the changes in the proteome in FSHD muscles and myogenic cell lines.

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 #
5U54HD060848-02
Application #
7917471
Study Section
Special Emphasis Panel (ZAR1)
Project Start
2009-09-01
Project End
2013-08-31
Budget Start
2009-09-01
Budget End
2010-08-31
Support Year
2
Fiscal Year
2009
Total Cost
$330,385
Indirect Cost
Name
Boston Biomedical Research Institute
Department
Type
DUNS #
058893371
City
Watertown
State
MA
Country
United States
Zip Code
02472
Leung, Doris G; Wang, Xin; Barker, Peter B et al. (2018) Multivoxel proton magnetic resonance spectroscopy in facioscapulohumeral muscular dystrophy. Muscle Nerve 57:958-963
Wallace, Lindsay M; Saad, Nizar Y; Pyne, Nettie K et al. (2018) Pre-clinical Safety and Off-Target Studies to Support Translation of AAV-Mediated RNAi Therapy for FSHD. Mol Ther Methods Clin Dev 8:121-130
Giesige, Carlee R; Wallace, Lindsay M; Heller, Kristin N et al. (2018) AAV-mediated follistatin gene therapy improves functional outcomes in the TIC-DUX4 mouse model of FSHD. JCI Insight 3:
Chagarlamudi, Hema; Corbett, Alastair; Stoll, Marion et al. (2017) Bone health in facioscapulohumeral muscular dystrophy: A cross-sectional study. Muscle Nerve 56:1108-1113
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
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:
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
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

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