PRINCIPAL INVESTIGATOR: Wendy M. Mars, Ph.D. - Associate Professor of Pathology Office: Rm. 411B, S-BST 200 Lothrop Street Pittsburgh, PA 15261 Email: wmars@pitt.edu Tel: 412-648-9690 Fax: 412-648-1916 Assistant: Shari Tipton Tel: 412-648-9550 Email: tiptonsl@upmc.edu Lab: S454-BST 200 Lothrop Street Pittsburgh PA 15261 Tel: 412-383-7840    RESEARCH: About the Principal Investigator: Dr. MARS obtained her undergraduate degree in Medical Technology at Arizona State University and later went on to pursue her Ph.D. from the University of Texas M.D. Anderson Cancer Center, studying gene expression in Chronic Myelogenous Leukemia under the guidance of Dr. Grady Saunders. She then did a postdoctoral fellowship on the genetics of breast cancer in the laboratory of Dr. David Anderson at the University of Texas School of Public Heath before moving to Pittsburgh. In 1991, Dr. Mars moved to the department of Pathology as a Research Associate with Dr. George Michalopoulos. Subsequently, she was promoted to Assistant Professor and then Associate Professor. Since 2006 she has served as the Director of the Cellular and Molecular Pathology (http://path.upmc.edu/cmp/00.htm) CMP graduate program in the School of Medicine Interdisciplinary Program (http://www.gradbiomed.pitt.edu/) where she serves as the Preceptor Coordinator for the core Foundations course. Dr. Mars is also the course director for the CMP graduate course entitled Pathology Research Seminar and has been director of the Summer Undergraduate Research Program for CMP (http://path.upmc.edu/cmp/cmp-sum.htm) since 2003. In 2000 she co-founded the Pathology Post-doctoral Research Training Program (http://path.upmc.edu/pprtp/index.htm) that is currently run by Dr. Aaron Bell . Ongoing Research: The general focus of the laboratory is to utilize regenerating liver as a NORMAL model for understanding how the plasminogen activator system contributes to the development of diseases such as CANCER. In the rat, liver regeneration is at least partially dependent upon a growth factor known as hepatocyte growth factor (HGF). HGF can be activated in vitro by the urokinase-type and tissue-type plasminogen activators (u-PA and t-PA); however, in vivo only u-PA seems to be important for compensatory liver regeneration in the rat. These proteins are part of a "system" which includes selected receptors (for example the u-PA receptors, u-PAR and LRP), inhibitors (for example, the type 1 plasminogen activator inhibitor or PAI-1), and substrates (such as plasminogen (Plg) and HGF). All if the members of this "system" have been implicated in cancer biology in some way or another; however, their roles in contributing to the cancer phenotype remain unclear. One way to approach this problem is to study these proteins in a normal model of tissue regeneration such as regenerating liver. In order to further elucidate the role of this system in tissue regeneration, mice were obtained that have deletions in the genes encoding u-PA, t-PA, PAI-1, MET (the HGF receptor), and u-PAR (knockout mice), as well as mice that are "floxed" for the genes MET and LRP. These mice are being used to identify the roles of the various genes during regenerative and disease processes in the primary hepatic cell types (endothelia, hepatocytes, stellate cells, macrophages) by utilizing a combination of techniques. In particular, the lab is currently focusing on two primary projects: 1) the interactions between HGF and t-PA during the development of fibrosis and 2) the interactive regulation between HGF and IL-6.. ONLINE RESOURCES: Dr. Mars' CV Dr. Mars' NIH BIOGRAPHICAL SKETCH MEMBERS: Graduate Students: Liang-I Kang, (CMP student in MD/PhD program) Lab Manager: Callie Norris Others: Jennifer Sydeski Hurd, (Staff)? PUBLICATIONS: View Dr. Mars' publications on PubMed. Gkretsi, V., Apte, U., Mars, W.M., Bowen, W.C., Luo, J-H., Yang, Y., Yu, Y.P., St.-Arnaud, R., Dedhar, S., Kaestner, K., Wu, C., and Michalopoulos, G.K. Liver-specific ablation of integrin linked kinase in mice results in abnormal liver histology, enhanced cell proliferation and hepatomegaly. Hepatology, 48, 1932-1941 (2008). Hu, K., Lin, L., Tan, X., Mars, W.M., and Liu, Y. Tissue-type plasminogen activator is a survival factor that protects renal interstitial fibroblasts and myofibroblasts from apoptosis. J. Am. Soc. Nephrol. 19, 503-514 (2008). Hu, K., Wu, C., Mars, W.M. and Liu, Y. tPA promotes myofibroblast activation through LRP-1-mediated recruitment of integrin signaling. J. Clin. Invest. 117, 3821-3832 (2007). Gkretsi, V., Mars, W.M., Bowen, W.C., Barua, L., Yang, Y., Guo, L., St.-Arnaud, R., Dedhar, S., Wu, C., and Michalopoulos, G.K. Loss of Integrin Linked Kinase (ILK) from mouse hepatocytes in vitro and in vivo results in apoptosis and hepatitis. Hepatology 45, 1025-1034 (2007). Hu, K., Yang, J., Tanaka, S., Gonias, S.L., Mars, W.M., and Liu, Y. Tissue-type plasminogen activator acts as a cytokine that triggers intracellular signal transduction and induces matrix metalloproteinase-9 gene expression. J. Biol. Chem. 281, 2120-2127, (2006). Lagoa, C.E., Vodovotz, Y., Stolz, D.B. Lluillier, F., McCloskey, C., Gallo, D., Yang, R., Ustinova, E., Fink, M., Billiar, T.R. and Mars, W.M. Contribution of type 1 plasminogen activator inhibitor (PAI-1) to hepatic injury during hemorrhagic shock. Hepatology 42, 390-399 (2005). Mars, W.M. Jo, M. and Gonias, S.L. Activation of Hepatocyte Growth Factor by urokinase-type plasminogen activator is ionic strength-dependent. Biochem. J 390, 311-315 (2005). Schoedel KE, Tyner VZ, Kim TH, Michalopoulos GK, Mars WM. HGF, MET, and matrix-related proteases in hepatocellular carcinoma, fibrolamellar variant, cirrhotic and normal liver. Mod Pathol. 16, 14-21 (2003). Yang J, Shultz RW, Mars WM, Wegner RE, Li Y, Dai C, Nejak K, Liu Y. Disruption of tissue-type plasminogen activator gene in mice reduces renal interstitial fibrosis in obstructive nephropathy. J Clin Invest. 110, 1525-1538 (2002). Monga SP, Mars WM, Pediaditakis P, Bell A, Mule K, Bowen WC, Wang X, Zarnegar R, Michalopoulos GK. Hepatocyte growth factor induces Wnt-independent nuclear translocation of beta-catenin after Met-beta-catenin dissociation in hepatocytes. Cancer Res. 62, 2064-2071 (2002). Pediaditakis P, Monga SP, Mars WM, Michalopoulos GK. Differential mitogenic effects of single chain hepatocyte growth factor (HGF)/scatter factor and HGF/NK1 following cleavage by factor Xa. J Biol Chem. 277, 14109-14115 (2002).