Recent studies conducted in several countries have come to the unanimous conclusion that fibrinogen levels are a major risk factor for cardiovascular disease. The risk associated with elevated levels equals or exceeds the risk for serum cholesterol, high blood pressure, smoking, diabetes and obesity. Furthermore, the epidemiologic data suggest that elevated fibrinogen levels play a role in the pathogenesis of cardiovascular disease and correlate with a restriction polymorphism in the fibrinogen locus. Production of fibrinogen is in large part controlled by the transcription factor, hepatocyte nuclear factor 1 or HNF-1, which interacts with the control regions for the fibrinogen genes as well as other liver-specific genes. We have isolated a cDNA for HNF-1 and found that it contains a homeodomain similar to that found in genes responsible for pattern formation in invertebrates, and also is a distant member of the POU family of transcriptional activators. Our goal is to understand how this protein functions and how it is developmentally regulated. Specifically, we will begin by completing the sequencing of the cDNA and gene. This information will be used to dissect the functional regions of HNF-1 by analysis of alanine-substitution mutations and by using portions of HNF-1 to complement the function of well- characterized mutations is known transcriptional activators. The role of HNF-1 in hepatocyte differentiation and development will be explored by determining if expression of the protein in dedifferentiated cells leads to expression of endogenous fibrinogen genes. In a second approach we will determine if the inductive influences that are responsible for the formation of the liver and other organs operate by directly controlling HNF-1 n the developing embryo. Finally, we will make use of the observation that retinoic acid induces the production of HNF-1 in the F9 cell line to define the events that are required for the developmental regulation of HNF-1 and the molecules which cooperate with HNF-1 to activate liver-specific genes. At the end of this five year period, we hope to have characterize the cellular and molecular events that regulate HNF-1 during developing and to have a precise understanding of its role in organogenesis and the activation of the fibrinogen and other liver- specific genes.
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