Current Research:
Our laboratory is involved in two major areas of focus. The first involves studying the regulation, function and disease association of the cytoskeletal intermediate filament proteins that are specifically expressed in digestive-type epithelia. These proteins are termed keratin polypeptides 8, 18, 19 and 20 (K8/K18/K19/K20). The second area of focus involves studying the stress-inducible protein heme oxygenase-1 (HO-1) as a potential therapeutic target in acute pancreatitis. This is based on our findings that compounds that induce HO-1, such as hemin, protect from injury in two models of experimental acute pancreatitis.
Our keratin-related human disease association studies address understanding the importance of K8/K18/K19 mutations in predisposition to acute and chronic liver disease, and understanding the molecular pathogenesis and significance of the hepatocyte inclusions, Mallory-Denk bodies. We approach studying keratin regulation and function in the liver, intestine and pancreas by using genetic and molecular means that include the characterization of keratin posttranslational modifications (e.g., phosphorylation and glycosylation) and keratin associated proteins such as members of the 14-3-3 family that play important roles in cell signaling.
The studies pertaining to HO-1 include assessment of its modulation in human acute pancreatitis, and understanding the mechanism of protection upon HO-1 induction which relates to unique leukocyte subset homing to the pancreas. The animal studies to date provide encouraging support for potential therapeutic and prophylactic applications to human acute pancreatitis.
Representative Publications:
Zhou Q, Cadrin M, Herrmann H, Feng L, Chen C-H, Chalkley R, Burlingame A and Omary MB (2006). Keratin 20 serine-13 phosphorylation is a stress and intestinal goblet cell marker. /J Biol Chem/ 281:16453-61
Ku N-O and Omary MB. (2006). A disease and phosphorylation related non-mechanical function for keratin 8. /J Cell Biol/ 174:115-25
Omary MB, Ku NO, Tao GZ, Toivola DM and Liao J (2006). Heads-and-tails of intermediate filament phosphorylation: Multiple sites and functional insights. /Trends Biochem Sci/ 31:383-94
Strnad P, Harada M, Siegel M, Terkeltaub RA, Graham RM, Khosla C, and Omary MB (2007). Transglutaminase 2 regulates Mallory body inclusion formation and injury-associated liver enlargement. /Gastroenterology/ 132:1515-1526
Zhong B, Strnad P, Toivola DM, Tao GZ, Ji X, Greenberg HB and Omary MB. (2007). Reg-II is an exocrine pancreas injury-response product that is up-regulated by keratin absence or mutation. /Molec Biol Cell/ 18:4969-4978
Ku N-O, Strnad P, Zhong B, Tao GZ and Omary MB (2007). Keratins let liver live: mutations predispose to liver disease and crosslinking generates Mallory-Denk bodies. /Hepatology/ 46:1639-49
Strnad P, Tao G-Z, Zhou Q, Harada M, Toivola DM, Brunt EM and Omary MB. (2008). Keratin mutation predisposes to mouse liver fibrosis and unmasks differential effects of the CCl_4 and thioacetamide models. /Gastroenterology/ 134:1169-1179
Toivola DM, Nakamichi I, Strnad P, Michie SA, Ghori N, Harada M, Zeh K, Oshima RG, Baribault H, Omary MB. (2008). Keratin overexpression levels correlate with the extent of spontaneous pancreatic injury. /Am J Pathol/ 172:882-892
Harada M, Hanada S, Toivola DM, Ghori N, Yoshimori T and Omary MB. (2008). Autophagy activation by rapamycin eliminates mouse Mallory-Denk bodies and blocks their proteasome inhibitor-mediated formation. /Hepatology/ 47:2026-2035
Tao G-Z, Li DH, Toivola DM, Zhou Q, Strnad P, Sandesara N, Cheung RC, Hong A and Omary MB. (2008). Monitoring of epithelial cell caspase activation via detection of durable keratin fragment formation. /J Pathol/ 215:164-174
Yang A, Vadhavkar S, Singh G and Omary MB. (2008). Epidemiology of alcohol-related liver and pancreatic disease in the US. /Arch Int Med/ 168:649-656
Hanada S, Strnad P, Brunt EM, Omary MB. (2008). The genetic background modulates susceptibility to mouse liver Mallory-Denk body formation and liver injury. /Hepatology/ 48:943-952
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