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Research Interests:
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.
Selected Publications:
View Dr. Mars' publications on PubMed.
- Norris, C.A., He, M., Kang, L.-I., Yang, Y., Paranjpe, S., Spardy, N. Bowen, W.C., Orr, A., Michalopoulos, G.K., Stolz, D. B. and Mars, W.M. Production of interleukin-6 by hepatocytes as a general response to injury. (in preparation)
- Donthamsetty, S., Mars, W.M., Orr, A., Wu, C., and Michalopoulos, G. Protection Against Fas-induced Fulminant Hepatic Failure in Liver Specific Integrin Linked Kinase Knockout Mice (ePUB, Comparative Hepatology, 10:11, 2011)
- Lin, C-W, Mars, W.M., Paranjpe, S., Donthamsetty, S., Bhave, V.S., Kang, L.-I, Orr, A., Bowen, W.C., Bell, A., and Michalopoulos, G.K. Hepatocyte Proliferation and Hepatomegaly Induced by Phenobarbital and TCPOBOP is Suppressed in Hepatocyte-Targeted Glypican 3 Transgenic Mice. Hepatology 54, 620-630 (2011) PMID: 21574168, PMC
- Donthamsetty, S., Bhave, V., Kliment, C., Bowen, W., Mars, W.M., Bell, A., Wu, C., Michalopoulos, G.K., Excessive Hepatomegaly of Mice with Hepatocyte-Targeted Elimination of Integrin Linked Kinase Following Treatment by 1,4-bis [2-(3,5-dichaloropyridyloxy)] benzene. Hepatology 53, 587-595 (2011). PMID: 21274879, PMC3062106.
- Coudriet, G.M., He, J., Trucco, M., Mars, W.M. and Piganelli, J.D. Hepatocyte Growth Factor Modulates Interleukin-6 Production in Bone Marrow Derived Macrophages: Implications For Inflammatory Mediated Diseases. PLoS ONE 5 (11): e15384 (2010). PMID: 21072211, PMC2970559
- Hao, S., Shen, H., Hou, Y., Mars, W.M., and Liu, Y. tPA is a potent mitogen for renal interstitial fibroblasts: role of ?1 integrin/focal adhesion kinase signaling. A. J. Path. 177, 1164-1175 (2010). PMID: 20639453, PMC2928951
- Lin, L., Bu, G., Mars, W.M., Reeves, W.B., Tanaka, S., and Hu, K. tPA promotes renal interstitial fibroblast proliferation through LDL receptor-related protein 1-mediated p90RSK and GSK3beta signaling. Am. J. Path. 177, 1687-1696 (2010). PMID: 20724593, PMC2947266.
- Liu, B., Bell, A.W., Paranjpe, S., Bowen, W.C., Luo, J.-H., Mars, W.M., and Michalopoulos, G.K. Suppression of liver regeneration and hepatocyte proliferation in glypican-3 hepatocyte-targeted transgenic mice. Hepatology 52, 1060-1067 (2010). PMID: 20812357, PMC2936713
- Dawes, J., Liu, B., Mars, W., Michalopoulos, G., and Khillan, J.S. Multiple ovarian transplants to rescue a transgenic line of mice. Lab Animal 39, 191-193 (2010). PMID: 20485359.
- Donthamsetty, S., Bowen, W., Mars, W., Bhave, V., Luo, J.-H., Wu, C., Hurd, J., Orr, A., Bell, A., and Michalopoulos, G. Liver Specific Ablation of Integrin Linked Kinase (ILK) in Mice Results in Enhanced and Prolonged Cell Proliferation and Hepatomegaly after Phenobarbital Administration. Toxicological Sciences, 113, 358-366 (2010). PMID: 19920070
- Bae, M.H., Bissonette. G.B., Mars, W.M., Michalopoulos, G.K., Achim, C., Depireux, D.A. and Powell, E.M. Hepatocyte Growth Factor (HGF) modulates GABAergic inhibition and seizure susceptibility. Experimental Neurology 221, 129-135 (2010). PMID: 19853606
- Apte, U., Gkretsi, V., Bowen, W.C., Mars, W.M., Luo, J-H., Donthamsetty, S., Orr, A., Monga, S.P.S., Wu, C., and Michalopoulos, G.K. Enhanced liver regeneration following changes induced by hepatocyte-specific genetic ablation of integrin-linked kinase. Hepatology 50, 844-851 (2009). PMID: 19575460
- Liu, B., Paranjpe, S., Bowen, W.C., Bell, A.W., Luo, J., Mars, W.M., Michalopoulos, G.K. Investigation of the Role of Glypican 3 in Liver Regeneration and Hepatocyte Proliferation. Am. J. Path., 175, 717-724 (2009). PMID 19574424, PMC2716967
- 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).
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