Modulation of RNA Binding Proteins in Xenobiotic-induced Hepatotoxicity

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Project Summary Approximately 33% of the nearly 700 workplace chemicals identified in the National Institute of Occupational Safety and Health (NIOSH) Pocket Guide are associated with hepatotoxicity. Several of these have been linked to increased liver disease mortality in workers in different occupational settings such as heavy construction equipment operators, chimney sweepers, and chemical workers. Xenobiotic-induced hepatotoxicity is characterized by oxidative stress, inflammation, and fibrosis, which, in later stages, may result in hepatic failure and hepatocellular carcinoma (HCC). While transcriptional perturbations have been implicated in inflammation and fibrosis; the role of post-transcriptional regulation in the development of xenobiotic-induced hepatic inflammation and fibrosis is unclear. The tristetraprolin (TTP) family of RNA binding proteins (RBPs) including zinc finger protein 36 (ZFP36) commonly referred to as TTP, zinc finger protein 36 like 1 (ZFP36L1), and zinc finger protein 36 like 2 (ZFP36L2), are the key players in post-transcriptional regulation of a large number of inflammation-relevant mRNAs. These proteins bind to AU-rich elements (AREs) on the 3’untranslated regions (3’UTRs) of target mRNAs and promote their decay. TTP family RBPs are dysregulated in human HCC. Industrial chemicals including chlorpyrifos, tetrachlorodibenzo-p-dioxin (TCDD), and carbon tetrachloride (CCl4), also dysregulate the expression of TTP family RBPs. However, the downstream molecular and cellular effects of these dysregulations on the host remain unknown. In this proposal, we will test our novel hypothesis that xenobiotic-induced dysregulation of TTP family RBPs expression results in altered post-transcriptional regulation that determines the pathogenesis of hepatic inflammation and fibrosis. We will use CCl4-induced liver inflammation and fibrosis as a model of hepatotoxicity and test our hypothesis through three specific aims. In Aim 1, we will employ liver-specific ablations of the three RBPs in mice and novel “omics” approaches to test the pathogenic mechanisms by which these RBPs regulate xenobiotic-induced liver inflammation and fibrosis. Aim 2 will characterize the cellular and molecular mechanisms by which TTP family RBPs regulate epithelial- mesenchymal transition, a lead cause of fibrosis and tumor metastasis, and finally, Aim 3 will test whether increasing the expression of TTP family RBPs in the liver protects against xenobiotic-induced hepatic inflammation and fibrosis. The overall goal of the proposed research is to understand the role of TTP family RBP mediated post-transcriptional regulation in the pathogenesis of xenobiotic-induced hepatotoxicity. Successful completion of the proposed studies will have a significant impact on the mechanistic understanding of the pathophysiology of xenobiotic-induced liver disease and the potential identification of TTP family RBPs as endogenous anti-inflammatory/anti-fibrotic proteins whose activity could be possibly enhanced to delay or prevent the onset of liver failure.