Wnt/?-catenin signaling has come to the forefront in liver biology. Its role in liver development, regeneration &stem cells is beginning to be understood. We identified its role in liver regeneration &showed activation of the Wnt/?-catenin signaling immediately after partial-hepatectomy (PHx). This was observed as nuclear translocation of ?-catenin protein ensuring G1 to S transition mediated by factors such as Cyclin-D1. In addition, we identified highest ?-catenin expression during early stages of hepatic morphogenesis in liver development &showed that its absence led to compromise in hepatoblast expansion &differentiation into bile ducts &failure of hepatocyte maturation. Recently, we have also identified the role of Wnt/?-catenin in adult liver stem cells or oval cells, where this pathway regulates their emergence &expansion. As we have uncovered several key roles of this pathway, many new questions have arisen! Several of these are of high significance &have taken the form of the current proposal, which is a competing renewal of our previously funded application (1/1/2004-12/31/2008). In the current proposal we want to focus on three aspects of liver biology-development, regeneration &hepatocyte death. We have generated ?-catenin-conditional null mice (KO1) with Foxa3-Cre driven deletion of ?-catenin in hepatoblasts during development. This strategy unveiled the importance of ?-catenin in regulating hepatoblast expansion &differentiation. We propose to identify the molecular basis by which ?-catenin is regulating these two conceptually opposing events during development &hypothesize (based on stem cell paradigm) that differential interaction of ?-catenin occurs temporally with cofactors enabling transactivation of distinct genes that regulate the two processes. We will elucidate the basis of failed biliary differentiation in absence of ?-catenin &examine how lack of ?-catenin retards hepatocyte maturation. Based on the controversy in the role of Wnt/?-catenin signaling in hepatic specification in Zebrafish &Xenopus, we will utilize KO1 to address role of ?-catenin in murine hepatic specification. We have also generated ?-catenin-conditional-null mice (KO2) using Albumin-Cre &identified lack of proliferation in these mice at 40hrs (peak proliferation in controls) after PHx. We will address the molecular signaling in the absence of ?-catenin that enables a dramatic rescue of hepatocyte proliferation at 72hrs in KO2 mice. While we are beginning to understand the role of canonical Wnt signaling, the role & extent of noncanonical pathways-Wnt/Ca2+ &planar cell polarity pathways;remain obscure &will be investigated in-depth in liver development ®eneration. Finally, based on enhanced apoptosis in hepatocytes lacking ?-catenin, we investigated Fas-&TNF?-mediated injury in the KO2. Interestingly, while KO2 mice were clearly more susceptible to Jo-2 (Fas-ligand) injury than controls, they were resistant to lipopolysaccharide (LPS)-injury. The molecular basis of these findings will be elucidated. Thus, this proposal will be a comprehensive analysis of canonical &noncanonical Wnt signaling in hepatic biology.

Public Health Relevance

Understanding signaling pathways dictating the processes of liver growth, regeneration &development would be critical to identify the molecular basis of many hepatic diseases ranging from developmental anomalies to cancers &hepatic failure due to hepatitis, alcohol &other toxins. Our proposal will comprehensively examine Wnt signaling in liver biology to eventually improve prognosis of liver diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK062277-09
Application #
8217226
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Serrano, Jose
Project Start
2002-07-01
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
9
Fiscal Year
2012
Total Cost
$402,282
Indirect Cost
$133,095
Name
University of Pittsburgh
Department
Pathology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Ko, Sungjin; Monga, Satdarshan P (2018) Hepatic zonation now on hormones! Hepatology :
Russell, Jacquelyn O; Monga, Satdarshan P (2018) Wnt/?-Catenin Signaling in Liver Development, Homeostasis, and Pathobiology. Annu Rev Pathol 13:351-378
Thompson, Michael D; Moghe, Akshata; Cornuet, Pamela et al. (2018) ?-Catenin regulation of farnesoid X receptor signaling and bile acid metabolism during murine cholestasis. Hepatology 67:955-971
Pradhan-Sundd, Tirthadipa; Zhou, Lili; Vats, Ravi et al. (2018) Dual catenin loss in murine liver causes tight junctional deregulation and progressive intrahepatic cholestasis. Hepatology 67:2320-2337
Russell, Jacquelyn O; Lu, Wei-Yu; Okabe, Hirohisa et al. (2018) Hepatocyte-Specific ?-Catenin Deletion During Severe Liver Injury Provokes Cholangiocytes to Differentiate Into Hepatocytes. Hepatology :
Russell, Jacquelyn O; Ko, Sungjin; Saggi, Harvinder S et al. (2018) Bromodomain and Extraterminal (BET) Proteins Regulate Hepatocyte Proliferation in Hepatocyte-Driven Liver Regeneration. Am J Pathol 188:1389-1405
Preziosi, Morgan; Monga, Satdarshan P (2018) Novel Genetic Activation Screening in Liver Repopulation and Cancer: Now CRISPR Than Ever! Hepatology 68:408-411
Pradhan-Sundd, Tirthadipa; Vats, Ravi; Russell, Jacquelyn O et al. (2018) Dysregulated Bile Transporters and Impaired Tight Junctions During Chronic Liver Injury in Mice. Gastroenterology 155:1218-1232.e24
Zhan, Na; Michael, Adeola Adebayo; Wu, Kaiyuan et al. (2018) The Effect of Selective c-MET Inhibitor on Hepatocellular Carcinoma in the MET-Active, ?-Catenin-Mutated Mouse Model. Gene Expr 18:135-147
Soto-Gutierrez, Alejandro; Gough, Albert; Vernetti, Lawrence A et al. (2017) Pre-clinical and clinical investigations of metabolic zonation in liver diseases: The potential of microphysiology systems. Exp Biol Med (Maywood) 242:1605-1616

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