- Baylor College of Medicine (Office)
- BCM-MD Anderson Hall Room: BCMA-322B Mail Stop: BCM125 Houston, Texas 77030 United States
- Predoctoral Fellow
- Biochemistry - Cooper Lab
- Baylor College of Medicine
- Houston, TX, US
- BA from Rollins College
Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy in adults. Skeletal muscle wasting is a primary cause of mortality in DM1, yet the cause of muscle wasting remains unknown. The main goal of my project is to determine how the RNA binding protein CUGBP Elav-like family (CELF1) contributes to muscle wasting in DM1.
DM1 is caused by expansion of a CTG repeat in the 3' untranslated region of the Dystrophia Myotonica-Protein Kinase (DMPK) gene. The primary cause of pathogenesis is the expanded repeat (CUGexp) RNA expressed from the expanded allele. The CUGexp RNA accumulates in nuclear foci and affects the functions of at least two families of RNA binding proteins: muscleblind-like (MBNL) and CUGBP Elav-like family (CELF). MBNL is sequestered on CUGexp RNA foci producing a loss of function. The contribution of MBNL to myotonic dystrophy has been well established through the generation of MBNL knockout mice.
In addition, CUGexp RNA induces post-transcriptional up regulation of CELF1, producing a gain of function. Our lab has previously generated inducible transgenic mice that overexpress CELF1 in adult skeletal muscle to demonstrate that CELF1 up regulation is pathogenic and reproduces DM1-like muscle phenotypes, including muscle wasting and dystrophic muscle histology. CELF1 functions in the nucleus as a splicing regulator and in the cytoplasm as a regulator of mRNA stability and translation. Previous results from the Mahadevan lab illustrated that a Celf1-/- background partially rescued muscle pathology in a DM1 mouse model and affected CELF1 cytoplasmic targets but not nuclear. However, it is unknown to what degree CELF1 up regulation contributes to DM1 pathogenesis. The main goal of my project is to generate transgenic mice that inducibly express CELF1 specifically in adult skeletal muscle that localize either to the nucleus or cytoplasm to determine whether a gain of function of CELF1 nuclear and/or cytoplasmic function(s) contributes to DM1 pathogenesis. Transgenic lines have been generated and characterization of molecular and phenotypic effects is underway.
- Cox DC, Cooper TA. "Non-canonical RAN Translation of CGG Repeats Has Canonical Requirements." Mol. Cell. 2016 April 21 Pubmed PMID: 27105111