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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Specialized Center--Cooperative Agreements (U54)
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Boston Biomedical Research Institute
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