Superfund site toxicants pose a significant hazard to human health, in part through their ability to alter patterns of gene expression. One of the most prevalent diseases, toxicant-associated steatohepatitis (TASH), is phenotypically similar to nonalcoholic steatohepatitis (NASH) without the underlying obesity. Building on this similarity, this project will provide mechanistic insight into TASH-induced liver damage and models of exposure. With a focus on the epigenetic and immune responses, the overall goal of the project is to identify potential intervention or prevention therapies and/or therapeutic targets.
In Aim 1 we will explore the role of regulatory enhancers, key genomic mediators of tissue fibrosis, in mouse models of TASH by mapping injury-induced epigenetic changes in stellate cells, hepatocytes, and immune cells. In parallel studies, the therapeutic efficacy of epigenetically-targeted small molecule modulators will be determined in both intervention and prevention models of TASH.
In Aim 2 we will profile the immune response to toxicant-induced liver damage in mice during the initial injury, damage/repair, and resolution stages. Based on these findings, potential immune-targeted therapies for the treatment TAFLD and TASH will be explored.
In Aim 3, the epigenetic and immunological consequences of chronic toxicant exposure will be explored in a novel genetic mouse model of TAFLD (SMRTRID mice). In summary, this project will provide valuable insight on the molecular mechanisms underlying TAFLD and TASH as well as a roadmap for potential new therapies.
This project is directed at characterizing the molecular and genetic bases of liver damage caused by toxicant exposure. The project will also evaluate the efficacy of pharmacological agents in minimizing the damage induced by toxicant exposure in both preventive and intervention preclinical settings, and will thereby aid in the development of new diagnostics and therapeutics for combating toxicant exposure.
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