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Aberrant gene expression and muscular dystrophy: role of non-coding RNAs and alternative splicing in the pathogenesis and potential therapies (NCRNAS-SPLICING-FSHD)
Start date: Sep 1, 2008, End date: Aug 31, 2014 PROJECT  FINISHED 

Our goal is to characterize the molecular pathogenesis of facioscapulohumeral muscular dystrophy (FSHD) in order to develop possible therapeutic approaches. FSHD is the third most important myopathy. Currently, no therapeutic treatment is available for FSHD. Unlike the majority of genetic diseases, FSHD is not caused by mutation in a protein-coding gene. Instead, FSHD is the result of a complex epigenetic cascade activated by deletion of a 3.3 kb subtelomeric non-coding repeat (D4Z4) located on chromosome 4q35. D4Z4 appears to be required for maintaining proper chromatin structure at 4q35 and its deletion causes de-repression of several 4q35 genes. Recently, we found that FSHD is caused by over-expression of the 4q35 gene FRG1 and we generated the first animal model of the disease. Our specific aims are: 1. To elucidate the mechanism underlying control of gene expression at 4q35. Our preliminary results suggest that non-coding RNAs and micro-RNAs generated by D4Z4 regulate chromatin structure and 4q35 genes expression. Our analysis will generate novel insights into the biological role of repetitive DNA sequences in higher eukaryotes. 2. To identify the pathways affected by FRG1 over-expression. We have recently found that FRG1 over-expression causes aberrant alternative splicing of selective genes. Using splicing-sensitive microarrays we will identify FRG1-dependent alternatively spliced transcripts and validate them using the FSHD mouse model. Our studies will elucidate the role of alternative splicing in the pathogenesis and will identify targets for therapeutic purposes. 3. To search for a possible therapy for FSHD. Based on our finding, we propose independent strategies aimed at controlling FRG1 activity to interfere with the progression of muscular dystrophy. In summary, our studies will provide relevant information to understand the molecular basis of FSHD and will help the development of effective therapeutic strategies.
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