This is a revised renewal application for a grant, now in its 5th year, aiming to understand the role of HGF and signaling pathways in hepatic tissue assembly. Our recent studies have demonstrated that HGF and its receptor Met, as well as EGF receptor and the EGFR associated ligands) constitute the only two receptor tyrosine kinases capable of delivering a mitogenic signal to hepatocytes (in serum-free media and when administered to the whole animal, rat or mouse). We have also showed that HGF/Met and EGFR are the only two signaling systems capable of promoting transdifferentiation of hepatocytes to biliary epithelial cells in culture. These unique effects of HGF/Met and EGFR are highly significant. Many other receptor tyrosine kinases are expressed in hepatocytes and their ligands are capable of activating the cognate receptor, yet mitogenic signals are limited to HGF/Met and EGFR. We have recently applied short term knock down (KD) of either HGF/Met or EGFR by ShRNA and demonstrated that both have inhibitory effects on liver regeneration, that the one signal cannot compensate totally for the other, and that the effects are different in scope and complexity. KD of EGFR was followed by compensatory increases in other members of the ErbB family and upregulation of MET. In each instance, there was significant but not lethal activation of pro-apoptotic pathways. We further extend these studies in rats and performed a double KD of both HGF/Met and EGFR followed by partial hepatectomy (PHx). The result was complete liver failure, with massive apoptosis and necrosis of most hepatocytes and collapse of the hepatic parenchyma. This effect was not seen when double KD was performed without PHx. The proposed study will aim to determine the signals that lead to liver failure under the hypothesis that many cytokines involved in liver regeneration (e.g. TNF and TGFb1) can also function as agents that bring hepatocyte death and liver failure when the mitogenic signals of both EGFR and MET fail to function. In addition to the experimental studies, we will also analyze expression and status of activation of the above receptors as well cytokines capable of inducing hepatocyte death and liver failure in human liver material obtained from cases of fulminant hepatic necrosis.. Finally we will assess the importance of the compensatory mechanisms emerging after KD of EGFR and determine whether abrogation of these mechanisms is capable to also lead to liver failure by itself. The combination of these studies may allow us to understand the mechanisms that lead to massive hepatic necrosis as an aberrant dis-coordination of the early signals involved in liver regeneration and allow design of therapeutic interventions for prevention of massive hepatic necrosis based on rational mechanistic schemes.
/RELEVANCE The proposed studies aim to bring to bear the knowledge gained from liver regeneration to the elucidation of the pathways leading to liver failure. Fulminant hepatic failure (FHF) remains as one of the most lethal and costly human diseases curable only by liver transplantation. The failure of the liver to regenerate and the potential failure of the two mitogenic receptors (EGFR and MET) in combination with altered pathways involved in regeneration that can also induce hepatocyte apoptosis (e.g. TNF) are very likely to provide rational mechanistic understanding and therapeutic options in management of this serious clinical problem.
|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|
|Michalopoulos, George K; Khan, Zahida (2015) Liver Stem Cells: Experimental Findings and Implications forÂ Human Liver Disease. Gastroenterology 149:876-82|
|Bowen, William C; Michalopoulos, Amantha W; Orr, Anne et al. (2014) Development of a chemically defined medium and discovery of new mitogenic growth factors for mouse hepatocytes: mitogenic effects of FGF1/2 and PDGF. PLoS One 9:e95487|
|Michalopoulos, George K (2014) The liver is a peculiar organ when it comes to stem cells. Am J Pathol 184:1263-7|
|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|
|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|
|Nalesnik, Michael A; Tseng, George; Ding, Ying et al. (2012) Gene deletions and amplifications in human hepatocellular carcinomas: correlation with hepatocyte growth regulation. Am J Pathol 180:1495-508|
Showing the most recent 10 out of 30 publications