This grant is in its 25th year. It was initiated at a time prior to the discovery of HGF and its receptor c-t. The studies funded through the grant led to the discovery of HGF and its receptor and provided evidence that solidified the role of HGF/Met signaling as fundamental to initiation of regeneration and tissue assembly of liver. Studies supported by this grant also led to the findings on the role of extracellular matrix, urokinase, matrix metalloproteins and plasmin during the regenerative process, liver disease and hepatic neoplasia. The proposal continues on the overall theme of growth factors (HGF) and extracellular matrix interactions, and their role in liver regeneration. We are testing the hypothesis that signals generated from hepatic extracellular matrix are important for the f termination of regeneration. ECM signaling through integrins is mediated via Integrin Linked Kinase (ILK). Liver targeted elimination of ILK results in enhanced liver size and improper termination of regeneration. ILK -/- livers gain weight (30%!) at the end of the regenerative process. Studies are proposed to further define this finding and to begin to understand the mechanisms by which ECM, acting via ILK, controls restitution of the final size of the regenerated liver to the original normal size prior to partial hepatectomy. ECM is a complex mixture of heavily substituted proteins, some truly extracellular and some anchored on the plasma membrane. In order to identify the ECM components relevant to the delivery of the regeneration termination signal, we focused on a protein known as Glypican-3 (GPC3) which is the most over-expressed protein in human liver cancer. GPC3 deletion in humans and mice results in diffuse organ over-growth (Simpson-Golabi-Behmel syndrome). GPC3 expression increases at the end of liver regeneration and at the end of a growth cycle induced by HGF and EGF in cell culture. We are exploring the hypothesis that GPC3 is the most important component of the ECM matrix termination signal and we propose to test this hypothesis by using GPC3 knockout mice and liver-targeted GPC3 transgenic mice. The above studies will continue to focus on interactive signaling between growth factors and matrix as very important in the regulation of regeneration of liver, with implications for regenerative potential in other tissues. Liver regeneration is an important aspect not only of healing liver injury, but also (when uncontrolled) in formation of cirrhosis and other forms of chronic liver damage.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA035373-27
Application #
7668750
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Jhappan, Chamelli
Project Start
1983-07-15
Project End
2012-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
27
Fiscal Year
2009
Total Cost
$329,101
Indirect Cost
Name
University of Pittsburgh
Department
Pathology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Bhushan, Bharat; Stoops, John W; Mars, Wendy M et al. (2018) TCPOBOP-Induced Hepatomegaly and Hepatocyte Proliferation Are Attenuated by Combined Disruption of MET and EGFR Signaling. Hepatology :
Koral, Kelly; Paranjpe, Shirish; Bowen, William C et al. (2015) Leukocyte-specific protein 1: a novel regulator of hepatocellular proliferation and migration deleted in human hepatocellular carcinoma. Hepatology 61:537-47
Kang, Liang-I; Isse, Kumiko; Koral, Kelly et al. (2015) Tissue-type plasminogen activator suppresses activated stellate cells through low-density lipoprotein receptor-related protein 1. Lab Invest 95:1117-29
Michalopoulos, George K; Khan, Zahida (2015) Liver Stem Cells: Experimental Findings and Implications for Human Liver Disease. Gastroenterology 149:876-882
Norris, Callie A; He, Mu; Kang, Liang-I et al. (2014) Synthesis of IL-6 by hepatocytes is a normal response to common hepatic stimuli. PLoS One 9:e96053
Bhave, Vishakha S; Mars, Wendy; Donthamsetty, Shashikiran et al. (2013) Regulation of liver growth by glypican 3, CD81, hedgehog, and Hhex. Am J Pathol 183:153-9
Nejak-Bowen, Kari N; Orr, Anne V; Bowen Jr, William C et al. (2013) Gliotoxin-induced changes in rat liver regeneration after partial hepatectomy. Liver Int 33:1044-55
Donthamsetty, Shashikiran; Bhave, Vishakha S; Mars, Wendy M et al. (2013) Role of PINCH and its partner tumor suppressor Rsu-1 in regulating liver size and tumorigenesis. PLoS One 8:e74625
Hattoum, Alex; Rubin, Erin; Orr, Anne et al. (2013) Expression of hepatocyte epidermal growth factor receptor, FAS and glypican 3 in EpCAM-positive regenerative clusters of hepatocytes, cholangiocytes, and progenitor cells in human liver failure. Hum Pathol 44:743-9
Nejak-Bowen, Kari; Orr, Anne; Bowen Jr, William C et al. (2013) Conditional genetic elimination of hepatocyte growth factor in mice compromises liver regeneration after partial hepatectomy. PLoS One 8:e59836

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