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Research in my laboratory focuses on the biology of muscle regeneration as it relates to various inherited and acquired myopathic states. Satellite cells are stem-cell like cells which reside in skeletal muscle and are the main resource of repairing damaged skeletal muscle whether inflicted by trauma or genetic disorders. We are using a variety of animal models to study the relationship between impaired muscle regeneration and myopathic disease progression. It is our goal to characterize biological pathways which are crucial for satellite cell function. Ultimately, identification of these pathways will lead to the development of novel therapeutic strategies. We are also interested in the molecular pathogenesis of cardiomyopathies associated with muscular dystrophies. One focus has been to characterize altered signaling pathways in cardiac muscle which are amenable to pharmacological treatment.
Using a novel approach to understanding the mechanisms of maintaining muscle mass and regeneration, we have started to work with hibernating ground squirrels. Maintenance of normal muscle mass and physiology is essential for health. Disuse (e.g., immobilization, denervation, and microgravity) and aging result in debilitating loss of skeletal muscle. Loss of muscle mass is thought to be the net result of a decrease in satellite cell number and/or impaired proliferation, associated with increased muscle proteolysis and decreased protein synthesis. In stark contrast to the above, hibernating mammals have evolved mechanisms to survive prolonged immobility without pathologic loss/atrophy of muscle mass. The molecular mechanisms underlying this fascinating phenomenon are largely unknown. We are currently for the first time applying knowledge of normal mechanisms of muscle protection in the hibernating mammal to the disease process of disuse muscle atrophy in non-hibernating mammals. This will provide unique insights into the fundamental cellular and molecular pathways underlying skeletal muscle atrophy and the protection against it.
The Johns Hopkins Center for Hypotonia
Durbeej, M, Cohn RD, Hrstka RF, Moore SA, Allamand V, Davidson BL, Williamson RA, Campbell KP. Disruption of the b-sarcoglycan gene reveals pathogenetic complexity of limb-girdle muscular dystrophy type 2E. Mol Cell 2000;5:141-151
Flanigan KM, Kerrl, Bromberg MB, Leonard C, Tsuruda J, Zhang P, Gonzalez-Gomez I, Cohn RD, Campbell KP and Leppert M. Congenital muscular dystrophy with rigid spine syndrome: a clinical, pathological, radiological, and genetic study. Ann Neurol 2000;47:152-161.
Franz WM, Mueller M, Herrmann R, Frey N, Cohn RD, Voit T, Katus HA. Association of nonsense mutation of dystrophin with disruption of sarcoglycan complex in X-linked dilated cardiomyopathy. Lancet 2000;355:1781-1785
Cohn RD and Campbell KP. The molecular basis of muscular dystrophy. Muscle and Nerve 2000;23:1456-1471
Cohn RD and Campbell KP. Pathogenetic role of the sarcoglycan-sarcospan complex in cardiomyopathies. Acta Myologica 2000;19:171-180
Voit T, Kutz P, Leube B, Neuen-Jacob E, Schroeder JM, Cavallotti D. Vaccario ML, Schaper J, Broich P, Cohn RD, Baethmann M, Gohlich-Ratmann G, Scopetta C, Herrmann R. Autosomal dominant distal myopathy: further evidence of a chromosome 14 locus. Neuromuscul Disord. 2001;11:11-19.
Cohn RD, Durbeej M, Moore SA, Prouty S, Coral-Vasquez R, Campbell KP. Prevention of the cardiomyopathic phenotype in genetic mouse models with absence of the smooth muscle sarcoglycan complex. J Clin. Invest. 2001;107:R1-R7
Voit T, Kutz P, Leube B, Neuen-Jacob B, Schroder JM, Cavalotti D, Vaccario ML, Schaper J, Broich P, Cohn RD, Baethmann M, Gohlich-Rathmann G, Scopetta C, Herrmann R. Autosomal dominant distal myopathy: further evidence of a chromosome 14 locus. Neuromusc. Disord. 2001;11:11-19
Michele DE, Barresi R, Kanagawa M, Saito F, Cohn RD, Satz JS, Dollar J, Nishino I, Kelley RI, Somer H, Straub V, Mathews KD, Moore SA, Campbell KP. Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies. Nature 2002;418:418-421
Moore SA, Saito F, Chen J, Michele DE, Henry MD, Messing A, Cohn, RD, Ross-Barta SE, Westra S, Williamson RA, Hoshi T, Campbell KP. Deletion of brain dystroglycan recapitulates aspects of congenital muscular dystrophy. Nature 2002;418:422-425
Cohn RD , Henry MD, Michele DE, Barresi R, Saito F, Moore SA, Flanagan JD, Swarchuk MW, Robbins ME, Mendell JR, Williamson R, Campbell KP. Disruption of Dag1 in Differentiated Skeletal Muscle Reveals a Role for Dystroglycan in Muscle Regeneration. Cell 2002;110:639-648
Saito F, Moore SA, Barresi R, Henry MD, Messing A, Ross-Barta SE, Cohn RD, Williamson RA, Sluka KA, Sherman DL, Brophy PJ, Schmelzer JD, Low PA, Wrabetz L, Fletri ML, Campbell KP. Unique Role of Dystroglycan in Peripheral Nerve Myelination, Nodal Structure and Sodium Channel Stabilization. Neuron 2003;38:747-758
Cohn RD and Campbell KP. Pathogenesis of cardiomyopathy associated with muscular dystrophy. Chapter 12 in Chien KR. “Molecular basis of cardiovascular disease) 2004;306-310
Cohn RD. Muscle Brain Diseases. In Singer/Crawford/Kossof/Hartmann. “Treatment of Pediatric Neurologic Diseases” 2004
Barresi F, Michele DE, Kanagawa M, Harper HA, Dovico SA, Satz, JS, Moore SA, Zhang W, Schachter H, Dumanski JP, Cohn RD, Nishino I Campbell KP. LARGE can functionally bypass ?-dystroglycan glycosylation defects in distinct congenital muscular dystrophies. Nature Medicine 2004;10:696-703
Cohn RD. Invited Review: Dystroglycan: Important player in skeletal muscle and beyond. Neuromusc Disord 2005;15:207-217
Habashi HP, Judge DP, Holm TM, Cohn RD, Loeys BL, CooperTK, MyersL, Klein EC, LiuG, Calvi C, Podowski M, Neptune ER, Halushka MK, Bedja D, Gabrielson K, Rifkin DB, Carta L, Ramirez F, Huso DL, Dietz HC. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome Science 2006;312:117-121
Peddy SB, Vricella LA, Crosson JE, Oswald GL, Cohn RD, Halushka MK, Cameron DE, Valle D, Loeys BL. Infantile restrictive cardiomyopathy due to a mutation in cardiac troponin T gene. Pediatrics, 2006;117:1830-1833
Cohn RD, Eklund E, Bergner AL, Casella JF, Woods SL, Althaus J, Blakemore KJ, Fox HE, Hoover-Fong JE, Hamosh A, Braverman NE, Freeze HH Boyadjiev SA. Intracranial Hemorrhage as the Initial Manifestation of a Congenital Disorder of Glycosylation. Pediatrics 2006;118:e514-521
Cohn RD, Habashi JP, Loeys BL, Klein EC, Holm TM, Judge DP, Dietz HC. Angiotensin II type 1 receptor blockade prevents TGFb-induced failure of muscle regeneration in multiple myopathic states. Submitted
Cohn RD, Liang HY, Shetty R, Abraham T, Wagner KR. Myostatin Does not Function as a Major Inhibitory Factor in Cardiac Muscle Growth and Regeneration. Neuromuscular Disord. 2007;17:290-296
Habashi JP, Judge DP, Holm TM, Cohn RD, Loeys BL, Cooper TK, Myers L, Klein EC, Liu G, Calvi C, Podowski M, Neptune ER, Halushka MK, Bedja D, Gabrielson K, Rifkin DB, Carta L, Ramirez F, Huso DL, Dietz HC. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 2006;312:117-121
Ron Cohn, MD
McKusick-Nathans Institute of Genetic Medicine