REGULATION OF AN EXTRACELLULAR XENOBIOTIC RESPONSE GENE

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DESCRIPTION: (Adapted from the Investigator's Abstract) The ability of a tissue to withstand injury-inducing xenobiotics depends on the ability of cells to synthesize new gene products necessary for protection and repair. ApoJ, an evolutionarily conserved secretory glycoprotein capable of binding diverse hydrophobic molecules, has been cloned by multiple investigators studying new gene expression in tissues exposed to xenobiotic agents that induce injury or apoptosis. It has been proposed to play a role in cytoprotection during pathological conditions and is strongly expressed by cells that surround lesions. ApoJ is also expressed constitutively and developmentally in an interesting series of epithelial cells frequently at the interfaces of fluid-tissue boundaries. Thus, apoJ is a gene expressed at critical biological interfaces in both normal and pathophysiologic circumstances. To test the hypothesis that apoJ promotes extracellular injury repair, the investigators propose to characterize injury repair in apoJ-null knockout mice that they have generated. Since many genes are activated by xenobiotic tissue injury, apoJ will serve as an ideal model to define mechanisms for gene induction by tissue injury. The first specific aim will test the hypothesis that apoJ has a cytoprotective function at sites of xenobiotic tissue injury. To do this, the ability of apoJ null knock-out and wild type mice to withstand xenobiotic tissue injury will be compared. Additionally, apoJ's role in kidney, brain, and male reproductive tract injury models in which three different chemical agents induce both tissue specific injury and apoJ expression will be evaluated. Because of its inducibility in many tissues by a wide variety of xenobiotic agents, it is hypothesized that a common mechanism controls gene activation by xenobiotic injury. To test this hypothesis the investigators will use chimeric apoJ-CAT reporter transgenes to identify sequences and elements of the apoJ gene responsible for activating gene expression in the three injury models to be studied in aim 1. If the same control sequences are responsible for the responsiveness to each injury in each tissue, this will suggest that the apoJ gene can serve as a prototype for the identification of novel and fundamental injury response mechanisms. Knowledge gained from these studies will define the importance of apoJ in injury response, provide a foundation for its combination with several other gene knock-outs likely to affect injury response at boundary interfaces, and will allow the identification of important genetic mechanisms that allow cells to respond to and withstand injurious effects of xenobiotics in the context of the intact animal.