Notch Signaling and Cell Fate in Embryonic and Adult Liver

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DESCRIPTION (provided by applicant): The liver is a complex and essential tissue. Its multiple functions are facilitated by an intricate three- dimensional organization of the two major "parenchymal" cell types of the liver - hepatocytes and cholangiocytes - relative to blood vessels. Cirrhosis disrupts the normal architectural arrangement of these cells, thereby interfering with the normal flow of blood and bile and preventing productive regeneration of the liver. The clinical consequences of cirrhosis - liver failure and liver cancer - result in thousands of deaths and billions of dollars in health care costs within the United States annually. The long-term objective of this work is to understand how liver differentiation and morphogenesis is normally controlled during development, and to apply this knowledge to innovative new strategies for liver regeneration, both in vivo and ex vivo. Previous work has suggested that Notch - a highly conserved receptor signaling pathway that is widely used during embryogenesis to control differentiation - plays an important role in liver development. Specifically, both human patients and mutant mice with deficiencies in Notch signaling exhibit abnormalities in bile ducts. It is unknown whether such abnormalities in differentiation or morphogenesis. The goal of this proposal is to determine the mechanism of Notch action during liver development and to reveal whether Notch signaling plays a role in the adult liver. These objectives will be achieved through the use of genetically engineered mice and cultured cell lines through three specific aims. First, the normal lineage relationship of cells within the developing liver will be determined. Second, the cellular effects of Notch activation within various compartments of the embryonic and adult liver will be determined. Third, cell culture methods for studying Notch's role in differentiation will be developed. These experiments should provide greater understanding of the mechanism of Notch activity in liver development. Moreover, they will provide a framework for future translational studies aimed at augmenting liver regeneration and morphogenesis in vivo and recapitulating liver development in vitro. Outline for lay audience: The goal of regenerative medicine is to replace a failing tissue with a functioning one by introducing necessary cells into an appropriate environment. The ultimate goal of this research proposal is to devise rational approaches to liver regeneration for use in therapy. As a first step, Notch signaling will be studied to understand how this essential signaling pathway functions during liver development and in the normal function of the liver.