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The Cohen-Steinbrecher lab focuses on two main areas: intestinal pathogens and the intestinal epithelial cell layer.
In an effort to understand host pathogen interactions and intestinal secretion, current research is investigating the mechanism of E. coli heat stable enterotoxin and its receptor guanylate cyclase-C (GC-C). This receptor also binds the endogenous mammalian peptides, guanylin and uroguanylin, that are produced in the intestine.
We have generated two knockout strains of mice, one with a deletion of the guanylin gene and the other with a deletion of the uroguanylin gene. We are using these mice as well as GC-C knockout mice to identify other receptors for these peptides and to test the hypotheses that guanylin and uroguanylin mediate the response to intestinal inflammation in addition to their effects on intestinal secretion. These peptides have potential clinical roles in the treatment of both irritable bowel syndrome and inflammatory bowel disease.
We are also working to understand how cytoplasmic signaling pathways and gene expression are regulated in the intestine and to determine how this relates to the pathogenesis of enteric inflammation and cancer.
Our primary focus is the epithelial cell layer that lines the interior of the intestine. This single layer of cells mediates not only fluid, electrolyte and nutrient absorption but also interacts with a highly complex microbial community found in the gut lumen. Deregulated signal transduction cascades and gene expression in the epithelial cell layer that result in disruption of these processes often result in intestinal inflammatory disease or cancer.
Our group studies two specific aspects of epithelial cell biology. First, collaborative studies are aimed at determining how guanylate cyclase proteins and the second messenger, cGMP, control epithelial layer barrier function and gene expression. Second, we are investigating the role of a cellular signaling protein called GSK-3β in coordinating the interplay between multiple signal transduction pathways and transcription factors that control intestinal development, inflammation and tumorigenesis.
Bryant AP, Busby RW, Cordero EA, Hannig G, Kessler MM, Pierce CM, Solinga RM, Tobin JV, Mahajan-Miklos S, Cohen M, Kurtz CB, Currie MG. Linaclotide is a potent and selective guanylate cyclase C agonist that elicits pharmacological effects locally in the gastrointestinal tract. Life Sciences. 86(19-20): 760–765. 2010.
Walker WA, Sherman P, Shneider BL, Cohen M, Barnard J. State of research in pediatric gastroenterology, hepatology, and nutrition: 2010 and beyond. Gastroenterology. 138:411-416. 2010.
Eutamene H, Bradesi S, Larauche M, Theodorou V, Mayer EA, Fioramonti J, Cohen M, Bryant AP, Kurtz C, Currie MG, Bueno L. Guanylate cyclase C-mediated antinociceptive effects of linaclotide in rodent models of visceral pain. Neurogastroenterol Motil. 22:312-e84. 2010.
Steinbrecher KA, Horowitz N, Harmel-Laws E, Finkelman FD, Flick MJ, Pinkerton MD, Witte DP, Blevins EA, Barney KA, Shaw MA, Palumbo JS. Colitis-associated cancer is dependent on the interplay between the hemostatic and inflammatory systems and supported by integrin alpha(M)beta(2) engagement of fibrinogen. Cancer Research. 70(7):2634-43. 2010.
Barnes MJ, Aksoylar H, Krebs P, Bourdeau T, Arnold CN, Xia Y, Khovananth K, Engel I, Sovath S, Lampe K, Laws E, Kronenberg M, Steinbrecher K, Hildeman D, Grimes HL, Beutler B, Hoebe K. Loss of T cell and B cell quiescence precedes the onset of microbial flora-dependent wasting disease and intestinal inflammation in Gimap5-deficient mice. J Immunol. 184(7):3743-54. 2010.
Munitz A, Cole ET, Waddell A, Groschwitz K, Ahrens R, Steinbrecher K, Willson T, Han X, Denson L, Rothenberg ME, Hogan SP. Paired immunoglobulin-like Receptor B (PIR-B) Negatively Regulates Macrophage Activation in Experimental Colitis. Gastroenterology. In Press, 2010.
Cohen MB. Clostridium difficile infections: emerging epidemiology and new treatments. J Pediatr Gastroenterol Nutr. 48 S2:S63-5. 2009.
Graham-Maar R, Heubi J, Cohen MB, Li B. Teaching and tomorrow: a novel recruitment program for a pediatric subspecialty. J Pediatr Gastroenterol Nutr. 49:594-598. 2009.
Garin-Laflam MP, Steinbrecher KA, Rudolph JA, Mao J, Cohen MB. Activation of guanylate cyclase C signaling pathway protects intestinal epithelial cells from acute radiation-induced apoptosis. Am J Physiol Gastrointest Liver Physiol. 296:G740-9. 2009.
Sellers ZM, Mann E, Smith A, Ko KH, Giannella R, Cohen MB, Barrett KE, Dong H. Heat-stable enterotoxin of Escherichia coli (STa) can stimulate duodenal HCO3(-) secretion via a novel GC-C- and CFTR-independent pathway. FASEB J. 22:1306-1316. 2008.
Steinbrecher KA*, Harmel-Laws E, Sitcheran R, Baldwin AS* (*Corresponding Authors). Loss of Epithelial RelA Results in Deregulated Intestinal Proliferative/Apoptotic Homeostasis and Susceptibility to Inflammation. J Immunol. 180(4):2588-99. 2008.
Alrefai WA, Jiang X, Katz JP, Steinbrecher KA, Cohen MB, Williams IR, Dudeja PK, Wu GD. Molecular cloning and promoter analysis of downregulated in adenoma (DRA). Am J Physiol. 293: G923–934. 2007.
Rudolph JA, Pratt J, Moura R, Steinbrecher K, Cohen MB. Novel mechanism of cyclic AMP mediated extracellular signal regulated kinase activation in an intestinal cell line. Cell Signal. 19:1221-1228. 2007.
Walker WA, Sherman P, Cohen M, Barnard J. State of pediatric gastroenterology, hepatology, and nutrition: 2006 and beyond. Gastroenterology. 132:434-436. 2007.
Konikoff MR, Blanchard C, Kirby C, Buckmeier B, Cohen MB, Heubi JE, Putnam PE, Rothenberg ME. Potential of blood eosinophils, eosinophil-derived neurotoxin, and eotaxin-3 as biomarkers of eosinophilic esophagitis. Clin Gastroenterol Hepatol. 4:1328-1336. 2006.
Konikoff MR, Noel RJ, Blanchard C, Kirby C, Jameson SC, Buckmeier B, Akers R, Cohen MB, Collins MH, Assa’ad AH, Aceves SS, Putnam PE, Rothenberg ME. A randomized, double-blind, placebo-controlled trial of fluticasone propionate for pediatric eosinophilic esophagitis. Gastroenterology. 131:1381-1391. 2006.
Wu W, Shin J, Zhang G, Cohen M, Franco M, Sears CL. The Bacteroides fragilis toxin binds to a specific intestinal epithelial cell receptor. Infect Immun. 74:5382-90. 2006.
Elitsur N, Lorenz JN, Hawkins JA, Rudolph JA, Witte D, Yang LE, McDonough AA, Cohen MB. The proximal convoluted tubule is a target for the uroguanylin-regulated natriuretic response. J Pediatr Gastroenterol Nutr. 43:S74-S81. 2006.
Blanchard C, Wang N, Stringer KF, Mishra A, Fulkerson PC, Abonia PJ, Jameson SC, Kirby C, Konikoff MR, Collins MH, Cohen MB, Akers R, Hogan SP, Assa’ad AH, Putnam PE, Aronow BJ, Rothenberg ME. Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis. J Clin Invest. 116 536-547. 2006.
Steinbrecher KA, Wilson W, Cogswell PC, Baldwin AS. Glycogen synthase kinase 3beta functions to specify gene-specific, NF-kappaB-dependent transcription. Mol Cell Biol. 25:8444-8455, 2005.
Anest V, Hanson JL, Cogswell PC, Steinbrecher KA, Strahl BD, Baldwin AS. A nucleosomal function for IkappaB kinase-alpha in NF-kappaB-dependent gene expression. Nature. 423:659-663. 2003.
Steinbrecher KA, Wowk S, Rudolph JA, Witte DP, Cohen MB. Targeted inactivation of the mouse guanylin gene results in altered dynamics of colonic epithelial proliferation. American Journal of Pathology. 161:2169-2178. 2002.
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