Utrophin (dystrophin related protein) shares extensive sequence homology and organizational motifs with dystrophin, and is considered to be the autosomal homolog of dystrophin. Indeed, transgenic over expression of utrophin can functionally substitute for the missing dystrophin molecule and reverse the dystrophic patho-physiology in the muscles of mdx (dystrophic) mice. The utrophin gene, while ubiquitously expressed, has a highly regulated sub-cellular distribution during development, regeneration as well as in mature skeletal muscle. In mature myofibers (elongated multi-nucleated cells), utrophin is enriched at the synapse or neuromuscular junction (NMJ). The spatial distribution of utrophin in myofibers parallels the distribution of nicotinic acetylcholine receptors (nACHR) to a remarkable degree, in particular, the manner in which they are influenced by the release of growth and differentiation factors (e.g. heregulin) from motor nerves. Selective enrichment of nACHR and utrophin at the NMJ occurs, in part, due to their messages being preferentially transcribed at sub-synaptic nuclei rather than nuclei scattered along the length of the myofiber. We and others, recently demonstrated that the neurite-associated growth factor heregulin utilizes the ERK (MAP kinase) signaling pathway to promote the binding of the GABPa/b transcription factor complex to the N-Box motif of the utrophin promoter, thus activating the promoter and increasing utrophin gene expression in cultured muscle cells. ? ? Current hypotheses on the regulation of utrophin expression in muscle center on N-box dependent compartmentalized transcription of utrophin at sub-synaptic nuclei. We hypothesize that additional trans-acting factors exist and regulate the utrophin promoter. We also hypothesize that co-operability among these trans-acting factors and signaling pathways plays a role in utrophin promoter regulation. In our preliminary studies, we have identified additional trans-acting factors, their signaling pathways and describe their co-operability in utrophin promoter regulation; we have also studied heregulin mediated utrophin promoter activation in mouse muscle, in vivo. In this proposal we plan to extend these studies to better understand the molecular mechanisms of utrophin promoter regulation in skeletal muscle. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR048871-06
Application #
7406122
Study Section
Special Emphasis Panel (ZRG1-SMB (01))
Program Officer
Nuckolls, Glen H
Project Start
2003-05-15
Project End
2010-04-30
Budget Start
2008-05-01
Budget End
2009-04-30
Support Year
6
Fiscal Year
2008
Total Cost
$286,646
Indirect Cost
Name
University of Pennsylvania
Department
Physiology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Moorwood, Catherine; Soni, Neha; Patel, Gopal et al. (2013) A cell-based high-throughput screening assay for posttranscriptional utrophin upregulation. J Biomol Screen 18:400-6
Amenta, Alison R; Yilmaz, Atilgan; Bogdanovich, Sasha et al. (2011) Biglycan recruits utrophin to the sarcolemma and counters dystrophic pathology in mdx mice. Proc Natl Acad Sci U S A 108:762-7
Pistilli, Emidio E; Bogdanovich, Sasha; Garton, Fleur et al. (2011) Loss of IL-15 receptor ýý alters the endurance, fatigability, and metabolic characteristics of mouse fast skeletal muscles. J Clin Invest 121:3120-32
Basu, Utpal; Lozynska, Olga; Moorwood, Catherine et al. (2011) Translational regulation of utrophin by miRNAs. PLoS One 6:e29376
Moorwood, Catherine; Lozynska, Olga; Suri, Neha et al. (2011) Drug discovery for Duchenne muscular dystrophy via utrophin promoter activation screening. PLoS One 6:e26169
Baby, Santhosh M; Bogdanovich, Sasha; Willmann, Gabriel et al. (2010) Differential expression of utrophin-A and -B promoters in the central nervous system (CNS) of normal and dystrophic mdx mice. Brain Pathol 20:323-42
Bogdanovich, Sasha; McNally, Elizabeth M; Khurana, Tejvir S (2008) Myostatin blockade improves function but not histopathology in a murine model of limb-girdle muscular dystrophy 2C. Muscle Nerve 37:308-16
Basu, Utpal; Gyrd-Hansen, Mads; Baby, Santhosh M et al. (2007) Heregulin-induced epigenetic regulation of the utrophin-A promoter. FEBS Lett 581:4153-8
Perkins, Kelly J; Basu, Utpal; Budak, Murat T et al. (2007) Ets-2 repressor factor silences extrasynaptic utrophin by N-box mediated repression in skeletal muscle. Mol Biol Cell 18:2864-72
Fraterman, Sven; Zeiger, Ulrike; Khurana, Tejvir S et al. (2007) Combination of peptide OFFGEL fractionation and label-free quantitation facilitated proteomics profiling of extraocular muscle. Proteomics 7:3404-16

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