Modulators of liver injury

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DESCRIPTION (provided by applicant): Alterations in pathways of programmed cell death, or apoptosis, may lead to a spectrum of liver diseases, ranging from acute hepatitis to end stage liver disease. Although effective therapies are not yet available for most of these liver disorders, studies have demonstrated that the restoration of hepatic parenchyma and homeostasis, following hepatic injury, is first initiated by proliferation of hepatocytes. Thus, the identification and functional delineation of hepatocyte-specific prosurvival modulators may provide a greater insight underlying hepatoprotective mechanisms. Among the hepatocyte-specific factors that have been implicated to play a role during liver repair and regeneration is the Insulin-like Growth Factor Binding Protein-1 (IGFBP1). Although the regulation of IGFBP1 gene expression in the regenerating liver has been extensively studied, the liver functions of IGFBP1 still are poorly understood. In previous studies designed to investigate how genetic disruption of IGFBP1 expression would affect hepatic function in vivo, we generated IGFBP1 knockout mouse. Our initial characterization of the IGFBP1-null mouse suggests that the IGFBP1-deficient liver has a pre-existing defect in apoptotic pathway. Additionally, we have obtained evidence that IGFBP1 functions as a prosurvival factor in the liver by modulating the mitochondrial apoptotic pathway. Thus, the proposed application will use biochemical, cell culture, and animal model systems to elucidate the interaction of IGFBP1 with other critical cellular factors to promote hepatic cell survival in response to particular stress signals. The interrelated specific aims will be performed under the guidance of a diverse team of experts with a strong track record of research in cancer biology, programmed cell death, liver biology, liver pathology, and computational structural biology. Additionally, the mentored research will enable the applicant to learn state-of-the-art molecular experimental and modeling techniques and to effectively transition to an independent research program investigating medically relevant research problems pertaining to liver metabolism and diseases.