The liver is the largest glandular organ in the body and is responsible for diverse functions including regulation of glucose and lipid metabolism, generation of bile, and detoxification of ingested substances. The primary cell type that is responsible for these functions is the hepatocyte. However, in order to generate a working liver the hepatocyes must function as part of community of liver cells. For these cells to properly interact they must be arranged in a specific format that produces the discreet of architecture of the liver that is so crucial for normal hepatic activity. Indeed, when the architecture of the liver is disrupted the liver cannot function resulting in hepatic failure. Hepatic architecture is produced during embryonic development when individual liver cells are generated and organize to produce tissues.
The aim of this proposal is to define the basic molecular processes that control development of the liver as an organ. This will achieved by studying mouse embryos and cells that lack a specific transcription factor, HNF4a, that is required for expression of over 600 hepatic genes. HNF4a is also an essential regulator of the epithelial transformation of the hepatic parenchyma during liver development. We porpose that HNF4a regulates liver development by both direct and indirect mechanisms.
The first aim will test whether HNF4a controls expression of such a large array of liver genes by regulating expression of a cascade of downstream transcription factors. In the second aim we will test whether HNF4 coordinates expression of genes encoding adhesion and cell junction proteins to elicit the epithelial transformation of the liver. Finally we will test whether it is neccessary for hepatic cells to form cell adhesions and junctions in order to control hepatocyte differentiation. Success in the proposed experiments will elucidate the fundamental mechanisms tha govern formation of the liver as an organ and will advance our ability to rationally generate and culture hepatocytes that have the potential to be used therapeutically.
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