This proposal is focused on morphogenesis of the biliary system, the conduit for transport of bile from hepatocytes to the intestine. Dysfunction of the bile ducts at any point along its intricate branched structure can be a source of morbidity and mortality, and re-establishment of normal biliary integrity is essential for recovery from injury. The experiments described in this proposal will provide insight into how connectivity is established along the entirety of the biliary tree, delineate the mechanisms by which Notch - a pathway whose deficiency causes bile duct deficiency in humans - regulates liver development, and determine the role of this pathway in the function of adult bile ducts. The long-term objective of this research is to understand how the liver achieves and maintains its three dimensional architecture. The proposed experiments will employ Cre/lox technology and real-time imaging to examine several parameters of biliary morphogenesis in vivo: formation of the extrahepatic-intrahepatic biliary junction, formation of the ductal-canalicular junction, and the establishment of biliary cell polarity and tubule formation. A central goal of the proposal is to test the hypothesis that Notch signaling controls bile duct development by initiating a cellular "tubulogenesis program," and specific candidate mediators of this process will be tested for their role in tubulogenesis in vitro. In addition, studies will be performed to examine how Notch signals are coordinated with other known regulators of bile duct development (e.g. HNF1b, HNF6, TGFb). Finally, experiments are proposed that will test the hypothesis that Notch signaling continues to exert an effect on liver biology throughout life, by maintaining ductal cell integrity and spatially organizing the response to injury.

Public Health Relevance

At present, the only effective treatment for patients with end-stage liver failure is transplantation. A major challenge to the development of alternative approaches is the inability to recapitulate normal liver cell organization (morphogenesis) and function outside of the body. The ultimate goal of this research is to delineate the events that guide differentiation and morphogenesis of the liver normally, and thereby devise rational approaches to liver regeneration and replacement.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Gastrointestinal Cell and Molecular Biology Study Section (GCMB)
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Sherker, Averell H
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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Gao, Tao; McKenna, Brian; Li, Changhong et al. (2014) Pdx1 maintains ? cell identity and function by repressing an ? cell program. Cell Metab 19:259-71
Moy, Ryan H; Gold, Beth; Molleston, Jerome M et al. (2014) Antiviral autophagy restrictsRift Valley fever virus infection and is conserved from flies to mammals. Immunity 40:51-65
Chen, Yi-Ju; Finkbeiner, Stacy R; Weinblatt, Daniel et al. (2014) De novo formation of insulin-producing "neo-? cell islets" from intestinal crypts. Cell Rep 6:1046-58
Rhim, Andrew D; Oberstein, Paul E; Thomas, Dafydd H et al. (2014) Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 25:735-47
Yimlamai, Dean; Christodoulou, Constantina; Galli, Giorgio G et al. (2014) Hippo pathway activity influences liver cell fate. Cell 157:1324-38
Wang, Ting; Yanger, Kilangsungla; Stanger, Ben Z et al. (2014) Cytokinesis defines a spatial landmark for hepatocyte polarization and apical lumen formation. J Cell Sci 127:2483-92
Yanger, Kilangsungla; Knigin, David; Zong, Yiwei et al. (2014) Adult hepatocytes are generated by self-duplication rather than stem cell differentiation. Cell Stem Cell 15:340-9
Gao, Tao; Zhou, Dawang; Yang, Chenghua et al. (2013) Hippo signaling regulates differentiation and maintenance in the exocrine pancreas. Gastroenterology 144:1543-53, 1553.e1
Yanger, Kilangsungla; Zong, Yiwei; Maggs, Lara R et al. (2013) Robust cellular reprogramming occurs spontaneously during liver regeneration. Genes Dev 27:719-24
Madison, Blair B; Liu, Qi; Zhong, Xue et al. (2013) LIN28B promotes growth and tumorigenesis of the intestinal epithelium via Let-7. Genes Dev 27:2233-45

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