This research proposal seeks to apply recent novel insights into cell signaling at the level of the plasma membrane (the caveolae/raft signaling hypothesis and the mitogen-caveolin-beta-catenin/cyclin D1 model) to an understanding of mechanisms of acetaminophen-induced liver injury and repair. There is now substantial evidence for a protective role of the macrophages and cytokines such as tumor necrosis factor-alpha (TNF-alpha), in acetaminophen toxicity. Caveolin-1-containing plasma membrane lipid rafts, or caveolae, are recognized as specialized organelles that sequester and negatively regulate various cell-signaling molecules, including the TNF-alpha receptor and many TNF-alpha receptor associated proteins, which are important in the actions of TNF-alpha. In rodent models, administration of toxic doses of acetaminophen results in liver macrophage activation, release of cytotoxic inflammatory mediators, and hepatocyte damage. This is followed by an accumulation of inflammatory macrophages in the liver, which release TNF-alpha. We have discovered that acetaminophen administration results in a marked down-regulation of caveolin-1 in the liver and the release of signaling molecules mediating hepatocyte proliferation and tissue repair. In preliminary studies we identified TNF-alpha as a major regulator of caveolin-1 expression in hepatocytes and a potent inducer of hepatocyte proliferation and tissue repair. The focus of the proposed studies is two-pronged: we plan to first evaluate our hypothesis that down regulation of caveolin-1 by TNF-alpha released from inflammatory macrophages is an initiating event in the repair of liver injury induced by acetaminophen; and second, we will investigate the role of caveolin-1 in hepatocyte repair processes mediated by TNF-alpha-induced activation of beta-catenin signaling.
Aim I will include investigations on the cellular and molecular mechanisms for down-regulation of caveolin-1 and the role of TNF-alpha in this process.
Aim II includes studies on the mechanisms of activation of beta-catenin by TNF-alpha and the role of caveolin-1 down regulation in this process.
Both Aims I and II will involve studies on caveolin-1 knockout mice and their response to acetaminophen. Mechanistic insights derived from these studies may suggest new therapeutic approaches in the treatment of acute liver injury induced by acetaminophen. ? ? ? ?
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