FSHD is one of the more common forms of muscular dystrophy in humans with a very unusual and poorlyunderstood biochemical, developmental and molecular underpinning. What is clear is that the D4Z4 repeatdeletion in some way influences the expression of genes in muscle in a dominant fashion to cause avariable degree of myofiber degeneration and muscle weakness in different patients. We have establishedby both proteomic and RNA profiling of muscle biopsies from FSHD patient that both proteins and RNAchange expression patterns in diseased tissue. In addition, we have observed in 5 FSHD families fromBrazil that some asymptomatic carriers of D4Z4 deletions substantially increase expression of 12 genesincluding 2 chemokines encoded on chromosome 4 which are only modestly changed in symptomaticpatients. We propose to follow up on these findings and use protein, microRNA and mRNA expressionprofiling as an approach to understanding the differences in disease severity in different individuals with theD4Z4 deletion with the hope that this understanding might lead to the discovery of biomarkers which will beuseful in evaluating potential treatments of FSHD. We propose to accomplish this goal according to thefollowing specific aims: 1) Continue to profile mRNA from FSHD patients, control muscle and cell linesgenerated 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 thechange in expression of the predicted targets of our observed miRNAs in the mRNA expression arrays fromaim 1. We will also ablate these candidate miRNAs in myogenic cell lines to see if we can recapitulate inculture the gene expression changes we see in skeletal muscle of FSHD patients. 3) Lastly, we will continueparallel experiments to define the changes in the proteome in FSHD muscles and myogenic cell lines.
Showing the most recent 10 out of 34 publications
