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James Hardwick Ph.D.

Associate Professor of Biochemistry/Molecular Biology

Integrative Medical Sciences

 

Phone: (330)325-6684

Location: F-141

 

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James P. Hardwick, Ph.D.

Associate Professor of Biochemistry/Molecular Pathology
Department of Integrative Medical Sciences
College of Medicine
jph@neomed.edu

Education

Ph.D., Biology - Biochemistry, Illinois State University, Normal, Ill. - 1981

M.S., Developmental Biology - Toxicology, Loyola University, Chicago, Ill. - 1978

B.A., Biology,  Illinois College, Jacksonville, Ill. - 1973

Professional Experience

Associate Professor of Biochemistry/Molecular Pathology, Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio - 1990-Present

Assistant Scientist, Adjunct Appointment Biomedical Research, Argonne National Laboratory, Argonne, Ill. - 1989-1991

Postdoctoral Fellow, Argonne National Laboratory, Argonne, Ill. - 1984-1989

Staff Fellow, National Institute of Environmental Health, Research Triangle Park, N.C. - 1982-1983

Postdoctoral Fellow, The McArdle Laboratory, University of Wisconsin, Madison, Wis. - 1981-1982 

Research Objectives

To understand the process of inflammation in human disease and the significance of fatty acid Omega hydroxylase genes (CYP4) in regulating inflammation and fatty acid metabolism.

Research Interests

The cytochrome P450 gene 4 family (CYP4) consists of a group of over 63 members that function to ω-hydroxylate the terminal carbon of fatty acids. In mammals, six subfamilies have been identified and three of these subfamily members show a preference in the metabolism of short (C7-C10)-CYP4B, medium (C10-C16)-CYP4A, and long (C16-C26)-CYP4F, saturated, unsaturated and branched chain fatty acids. These ω-hydroxylated fatty acids are converted to dicarboxylic acids, which are preferentially metabolized by the peroxiosome β-oxidation system to shorter chain fatty acids that are transported to the mitochondria for complete oxidation or used either to supply energy for peripheral tissues during starvation or used in lipid synthesis.

The differential regulation of the CYP4A and CYP4F genes during fasting, by peroxisome proliferators and in non-alcoholic fatty liver disease (NAFLD) and hepatocarcinogenesis suggests different roles in lipid metabolism. The ω-hydroxylation and inactivation of pro-inflammatory eicosanoids by members of the CYP4F subfamily and the association of the CYP4F2 and CYP4F3 genes with inflammatory Celiac disease indicate an important role in the resolution of inflammation. The close clinical association of Celiac disease with inflammatory disease of the liver; primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis, hemochromatosis, and fatty liver disease suggest that the CYP4 genes may play a vital functional role in the altered lipid metabolism and inflammation observed in these diseases.

Several human diseases have been genetically linked to the expression CYP4 gene polymorphic variants, which may link human susceptibility to diseases of lipid metabolism and the activation and resolution phases of inflammation. Understanding how the CYP4 genes are regulated during the fasting and feeding cycles and by endogenous lipids will provide therapeutic avenues in the treatment of metabolic disorders of lipid metabolism and inflammation. 

My current research is directed toward understanding the control and regulation of the CYP4 genes in fatty liver disease and its progress to steatohepatitis and hepatocarcinogenesis. In fatty liver disease, we hypothesize that induction of the CYP4A genes and uncoupling of the catalytic cycle by excess fatty acids results in increase reactive oxygen species, which is the second hit in the progression of steatosis to steatohepatitis. In contrast, the down-regulation of the CYP4F genes in liver results in both a altered oleic to stearic acid ratio leading to increased fatty acid accumulation in hepatocytes (first hit) and increased pro-inflammatory LTB4 levels leading to neutrophil recruitment to liver (second hit).

Extending this hypothesis to the progression of liver steatohepatitis to hepatocarcinogensis is evident. Down-regulation of CYP4F genes, which metabolize arachidonic acid and pro-inflammatory leukotrienes that recruit immune cells to sites of injury allows transformed cells to escape the host immunosurveillance system and thereby have a selective growth advantage. CYP4F1 gene expression is elevated in hepatic tumors, and cytochrome P4504F1 metabolizes the potent chemokinetic and chemotactic modulator of the inflammatory response, LTB4. Therefore, tumor cells expressing P4504F1 escape the immunological surveillance system.

Patents:

F.J. Gonzalez, H. Gelboin, U. Meyers, J.P. Hardwick, The sequence and expression of the human debrisoquine P450 hydroxylase gene application to human drug polymorphisms, 1991.

Recent Publications

Dr. Hardwick's publications listed in PubMed

Byoung-Joon Song, Mohamed A Abdelmegee, Lauren E. Henderson, Seong-Ho Yoo, Jie Wan, James P. Hardwick, Kwan-Hoon Moon. Mitochondrial dysfunction and fatty liver diseases studied with a redox proteomics approach. Journal of Proteomics. 2011, in press

James P. Hardwick, Byung-Joon Song, Eliezer Huberman, and Frank J. Gonzalez, Isolation, complementary DNA sequence, and regulation of rat hepatic lauric acid ω-hydroxylase (cytochrome P-450LAω). Identification of a new cytochrome P-450 gene family. Journal of Biological Chemistry Cytochrome;  P450 Classics, 2009.

Mohamed A. Abdelmegeed, Kwan-Hoon Moon, Frank J. Gonzalez, James P. Hardwick, and Byoung-Joog Song. Role of peroxisome proliferator-activated Receptor α in fasting-mediated oxidative stress. Free Radical Biology and Medicine 47:767-778, 2009.

Hardwick, J.P, Osie-Hyiaman, D, Wiland, H., Abdelmegeed, M.A.,
and Byoung J. Song. PPAR/RXR Regulation of Fatty Acid Metabolism and Fatty Acid Omega-hydroxylase (CYP4) Isozymes; Implications for Preventation of Lipotoxicity in Fatty Liver Disease. PPAR Research, ID 952734, 2009.

Hardwick, J.P
., and Chiang, JC.  PPARs, RXRs and Drug metabolizing enzymes. PPAR Research ID 589626, 2009

Hardwick, J.P
., Cytochrome P450 omega hydroxylase (CYP4) function in fatty acid metabolism and metabolic diseases. Biochemical Pharmacology , 75: 2263-2275, 2008

Donelson, Ellen, Liping Chen, Xiaolan Zhang, Puja Goswami, Byoung J. Song, James P. Hardwick. Genomic structure and regulation of the rat hepatic CYP4F1 Gene by peroxisome proliferators. Archives of Biochemistry and Biophysics, 472:1-16, 2008

Bong-Jo Kim, Brian L. Hood, Richard A. Aragon, James P. Hardwick, Thomas P.Conrads, Timothy D. Veenstra and Byoung J. Song. Increased oxidation and degradation of cytosolic proteins in alcoholic-exposed mouse liver and hepatoma cells. Proteomics, 6:1250-1260, 2006

Kwan-Hoon Moon, Brian L. Hood, Bobg-Jo Kim, James P. Hardwick, Thomas  P. Conrads, Timothy D. Veenstra, and Byoung J. Song. Inactivation of Oxidized and S-ntrosylated Mitochondrial Proteins in Alcoholic Fatty Liver of Rats. Hepatology, 44:1218-1230.2006

Zhang X., Chen L. and Hardwick J.P. Promoter activity and regulation of the CYP4F2 leukotriene B4 ω-hydroxylase gene by peroxisomal proliferators and retinoic acid in HepG2 cells. Arch. Biochem. Biophys. 378:364-376, 2000.

Zhang X. and Hardwick J.P. Regulation of CYP4F2 Leukotriene B4 ω-hydroxylase gene by retinoic acid in HepG2 cells. Biochem. Biophys. Res. Comm. 279:864-871, 2000.

Jeong K.-S., Shoh Y., Jeng J., Felder M.R., Hardwick J.P. and Song B.J. Cytochrome P4502E1 (CYP2E1) dependent production of a 37kda acetaldehyde protein adduct in rat liver. Arch. Biochem. Biophys. 384:81-87, 2000.

Chen L., Hardwick J.P., McPhie P., Sitkovsky M.V. and Jacobson ,K.A., Purification and recognition of recombinant mouse P2X1 receptors expressed in a baculovirus system. Drug and Development Research 51:7-19, 2000.

Narimatsu S., Kobayashi N., Masubuchi Y., Hardwick J.P., Gonzalez F.J. and Satoh T.  Enatioselectivity in the oxidation of propanolol was reversed between human and monkey liver microsomes. Chemico-Biologicial Interactions 127:73-90, 2000.