Dr. Nejak-Bowen is the Enrichment Director for the PLRC and a member of the Division of Experimental Pathology.
My primary current area of research is in understanding the molecular mechanisms of cholestatic liver disease, for which there are few effective medical therapies available. Specifically, we study the complex role of the Wnt/b-catenin signaling pathway in the progression of injury and fibrosis. The lab uses both innovative and well-established tools, including mouse models of biliary injury, fate tracing systems, small molecule therapeutics, imaging modalities, bioinformatics, and others, to study cholestasis. We has three projects in this area. 1) Previously, we identified an upregulation of Wnt signaling in several models of cholestasis, and showed that mice lacking Wnt signaling have decreased survival after injury. Conversely, mice expressing a non-degradable form of β-catenin in liver have an increased number of hepatocytes expressing cholangiocyte markers after cholestatic injury compared to wild-types, concurrent with increased bile flow and decreased biliary injury. In the first proposal, we are assessing the mechanism by which activation of the Wnt/b-catenin signaling pathway augments bile flow in a mouse model of chronic cholestasis, and whether b-catenin activation can accelerate creation of new biliary channels in models of bile duct paucity. 2) In the second proposal, we will use transcriptomics analysis to validate two mouse models that phenotypically resemble primary sclerosing cholangitis (PSC) and progressive familial intrahepatic cholestasis (PFIC), and determine the subset of PSC and PFIC cases they represent. We will also use these mouse models to assess the contribution of b-catenin to maintenance of cell polarity and cholangiocyte pathobiology in the context of cholestatic liver disease. 3) In the third project, we are studying the role of β-catenin in porphyrias, which are rare disorders caused by deficiencies in heme biosynthesis pathway enzymes. Previously, we showed that suppression of β-catenin led to lesser liver injury and biliary fibrosis in a mouse model of porphyria due to suppression of heme biosynthesis enzymes and induction of autophagy, which prevents accumulation of toxic protoporphyrins. In this proposal, we are assessing the mechanism by which inhibition of the Wnt/b-catenin signaling pathway provides protection from liver injury in a chemically-induced mouse model of porphyria, and whether b-catenin inhibition can prevent progression or provide protection in genetic mouse models of erythropoietic and acute intermittent porphyria.
NIH RePORT: https://reporter.nih.gov/search/WcEd9njKnkqLELa-sDnGJA/projects?projects=Active
- Ayers M, Liu S, Singhi AD, Kosar K, Cornuet P, Nejak-Bowen K. Changes in beta-catenin expression and activation during progression of primary sclerosing cholangitis predict disease recurrence. Sci Rep. 2022 Jan 7;12(1):206.
- Kosar K, Cornuet P, Singh S, Lee E, Liu S, Gayden J, Sato T, Freyberg Z, Arteel G, Nejak-Bowen K. WNT7B Regulates Cholangiocyte Proliferation and Function During Murine Cholestasis. Hepatol Commun. 2021 Dec;5(12):2019-2034.
- Kosar K, Cornuet P, Singh S, Liu S, Nejak-Bowen K. The thyromimetic GC-1 alters bile acid transport in a mouse model of hepatic cholestasis. Am J of Pathol. Am J Pathol. 2020 May;190(5):1006-1017.
- Pradhan-Sundd T, Kosar K, Saggi H, Zhang R, Vats R, Cornuet P, Green S, Singh S, Zeng G, Sundd P, Nejak-Bowen K. Wnt/β-catenin signaling plays a protective role in the Mdr2 KO murine model of cholestatic liver disease. Hepatology. 2020 May;71(5):1732-1749.
- Zhang R, Nakao T, Luo J, Xue Y, Cornuet P, Oertel M, Kosar K, Singh S, Nejak-Bowen K. Activation of Wnt/β-catenin signaling and regulation of the FXR/β-catenin complex after murine bile duct ligation. Hepatol Commun. 2019 Oct 14;3(12):1642-1655.
- Saggi H, Maitra D, Jiang A, Zhang R, Wang P, Cornuet P, Singh S, Locker J, Ma X, Dailey H, Abrams M, Omary MB, Monga SP, Nejak-Bowen K. Loss of hepatocyte β-catenin protects mice from experimental porphyria-associated liver injury. J Hepatol. 2019 Jan;70(1):108-117.
- Thompson MD, Moghe A, Cornuet P, Marino R, Tian J, Wang P, Ma X, Abrams M, Locker J, Monga SPS, Nejak-Bowen K. β-catenin regulation of farnesoid X receptor signaling and bile acid metabolism during murine cholestasis. Hepatology. 2018 Mar;67(3):955-971.