The liver is an epithelioid organ that can regenerate following partial hepatectomy, toxic damage or liver transplant. As such, it provides one of the few systems for analysis of mitogenesis in the fully developed, intact animal. Although it is comprised mainly of hepatocytes, the liver has a complex, multi-cellular architecture, implying that intercellular communications must exist during regeneration. Whereas multiple factors have been implicated, the growth factors involved in this process remain unknown. We have shown that one of the most highly expressed, immediate-early genes in liver regeneration encodes the rat homolog of the low molecular weight IGF binding protein (IGFBP-1). This protein has been found to enhance the mitogenic effect of IGF on tissues, and may act in a paracrine and/or autocrine fashion in maintaining normal liver architecture during regeneration. The goals of the research outlined in this proposal are first to determine the functional role of IGFBP-1 in hepatic development and regeneration, and second to analyze the regulation of expression of this gene during liver regeneration. These goals will be accomplished by completing the following specific aims: 1. Direct assessment of the mitogenic effects of IGFBP-1 and IGF-1 on hepatocyte and nonparenchymal liver cells in culture. 2. Further characterization of IGFBP-1 expression during liver development and regeneration by detection of IGFBP-1 and other IGFBPS, and by in situ detection of IGFBP-1 mRNA. 3. Examination of the transcriptional regulation of expression of the IGFBP-1 gene in insulin-treated H35 cells and in liver regeneration. 4. Genetic assessment of the role of IGFBP-1 in hepatic regeneration and development following underexpression of IGFBP-1 by gene """"""""knock out"""""""", and overexpression of IGFBP-1 in transgenic mice.
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