A major strength of the University of Rochester MDCRC is having a large group of highly motivated, well-characterized patients with myotonic dystrophy (DM1 & DM2) and facioscapulohumeral muscular dystrophy (FSHD), eager to support basic research and participate in clinical studies, and a group of enthusiastic investigators with a longstanding expertise in these diseases. These assets have led us to make """"""""The Dominantly Inherited Muscular Dystrophies: Pathophysiology and Treatment"""""""" the major focus of our 3 scientific projects and 2 scientific cores. Our primary emphases are on DM1 and FSHD. Project 1 explores the """"""""Role of RNA Toxicity and Muscleblind Proteins in the Pathophysiology of DM"""""""". Using muscleblind knockout mice and studies of alternative splicing of the skeletal muscle chloride channel Project 1 examines a toxic RNA model for the myotonic dystrophies. It tests the hypothesis that the abnormally expanded mRNA alleles in DM1 & DM2 sequester certain dsRNA-binding factors, the muscleblind proteins, and that this leads to myotonia and myopathy. Project 2 investigates a potential new treatment in DM1 and hopes to prove that SomatoKine (insulin-like growth factor-1 [IGF1] complexed with recombinant IGF binding protein-3) is safe, well-tolerated, and promising as a therapy. This project tests the hypothesis that deficient activation by IGF1 contributes to the atrophy in DM1, and that maintaining high blood levels of IGF1 will correct this deficiency. Project 3 strives to increase our knowledge of the molecular and cellular pathophysiology of FSHD. It uses microarray analysis of muscle biopsy specimens to test two hypotheses: in FSHD: a) deletion of D4Z4 heterochromatic repeats does not alter adjacent 4q35 genes; and, b) aberrant overexpression of smooth muscle genes is an important contributor to the pathophysiology. One Scientific Core is an Imaging Center. It provides specialized muscle histochemical and immunological techniques, fluorescent in situ hybridization, confocal microscopy, and electron microscopy. Projects 1 & 3 make extensive use of this Core. The other Scientific Core is a Repository of resources for research on Muscular Dystrophy. This Core maintains: a) myoblast cell lines for DM1 and FSHD; b) transgenic model cell lines; c) plasmids; d) antibodies; e) autopsy tissue DM1; and f) gene expression data on DM1 & FSHD patients. Projects 1, 2, & 3 interact with the Repository Core and this Core will interact with the other MDCRCs.
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