The human genome initiative and other lines of genomics research have engendered powerful new research tools, such as microarray analysis of gene expression and transgenesis in mice. The candidate has taken a leading role 'in developing a framework to incorporate these methods into patient-oriented research. He now seeks to extend this framework and devote more effort to mentoring new investigators in this underserved field. Myototuic dystrophy (DM), the most common inherited muscle disease in adults, has been adopted as a test case for this integrative approach. Although the pathophysiology of DM historicaly has been problematic, this approach is yielding rapid progress. DM is caused by expansion of a CTG repeat in the DM protein kinase (DMTK) gene. The repeat is located 'in a region that is transcribed (as a CUG repeat) but not translated into protein. The candidate has developed evidence that the pathogenic effect of the expanded repeat is mediated at the level of RNA: transcripts with an expanded CUG repeat do not leave the nucleus, they accumulate in the nucleus in multiple discreet foci, and they are sufficient to generate a DM phenotype in transgenic mice. This work establishes a novel, RNA-mediated disease mechanism, provides the first animal model for DIM, and lays the groundwork for farther progress through parallel studies of human DM and the transgenic model.
Aim I is to elucidate the mechanism of myotonia. Preliminary data indicate that expanded CUG repeats trigger aberrant splicing of a chloride channel mRNA and corresponding loss of chloride conductance in the muscle membrane. an alteration sufficient to cause myotonia.
Aim 2 is to undertake a broad search for genes whose expression is altered in human and murine DM. Preliminary data indicate strong activation of genes that are involved in the genotoxic stress response.
Aim 3 is to identify proteins that colocalize with, and may be sequestered by the expanded CUG repeats. One such protein, EXP42, has already been identified. EYCP42 is the human homologue of a gene that causes muscle disease when mutated in Drosophi1a, making it a strong candidate for involvement in the pathogenesis of DM.
Aim 4 is tit determine whether deficiency of DMPK enhances the toxicity of expanded CUG repeats, and to explore the possibility that the mechanical and biochemical stress of myotonia contributes to the degeneration of muscle fibers. information from this study may have a therapeutic application.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Midcareer Investigator Award in Patient-Oriented Research (K24)
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Special Emphasis Panel (ZAR1-TAS-C (O4))
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Nuckolls, Glen H
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University of Rochester
Schools of Dentistry
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Nakamori, Masayuki; Sobczak, Krzysztof; Puwanant, Araya et al. (2013) Splicing biomarkers of disease severity in myotonic dystrophy. Ann Neurol 74:862-72
Sobczak, Krzysztof; Wheeler, Thurman M; Wang, Wenli et al. (2013) RNA interference targeting CUG repeats in a mouse model of myotonic dystrophy. Mol Ther 21:380-7
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López Castel, Arturo; Nakamori, Masayuki; Thornton, Charles A et al. (2011) Identification of restriction endonucleases sensitive to 5-cytosine methylation at non-CpG sites, including expanded (CAG)n/(CTG)n repeats. Epigenetics 6:416-20

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