Liver-Related Work

Research Interests: For the past 15 years, my research has been focused on understanding the cellular and molecular basis of liver health and disease. Specifically, I am interested in understanding the role of signaling pathways such as Wnt/β-catenin in liver inflammation, injury, and cholestasis. I have recently identified a novel association of β-catenin with FXR that is unresponsive to bile acids or FXR agonists but sensitive to β-catenin inhibition. Based on this finding, I hypothesize that synergistic suppression of b-catenin and activation of FXR with an FXR agonist during cholestasis may alleviate injury and progression of cholestasis through optimal activation of FXR and subsequent inhibition of bile acid biosynthesis. This project is R01-funded (NIDDK). I am also elucidating the role of Wnt/β-catenin signaling in transdifferentiation of hepatocytes to cholangiocytes during chronic biliary injury. My goal is to ultimately apply my knowledge to the development of improved diagnostics and clinically relevant therapies in the treatment of cholestatic liver disease, particularly primary sclerosing cholangitis (PSC), a condition with a significant unmet clinical need.

Ongoing Research Studies:

1. Collaboration with Dr. Paul Monga, Vice Chair Division of Experimental Pathology, on the role of the Wnt/beta signalling pathway in cholestatic liver diseases, especially in hepatobiliary repair and transdifferentiation. 
2. Collaboration with Dicerna Pharmaceuticals for pre-clinical testing of β-catenin shRNA lipid nanoparticles in models of biliary fibrosis. 
3. Collaboration with Dr. Jake Demetris, Transplant Pathology, to analyze serial biopsies from post-transplant PSC patients for b-catenin localization as a surrogate for FXR activity. 

Available Tools:

Mouse models:

• Mdr2 KO (FVB background)
• Mdr2 KO (C57Bl/6 background) tamoxifen inducible Sox9-Cre
• S45D β-catenin-mutated mice (C57Bl/6 background)

Cell lines:

• Hep3B
• HepG2
• AML12
• primary mouse hepatocytes
• Raw264.7
• sm-cc (mouse-derived immortalized cholangiocytes)

Techniques:

• bile duct ligation
• liver perfusion

Associate Professor, Department of Pathology
Director of Enrichment Programs, Pittsburgh Liver Research Center