Liver fibrosis and ethanol: role of the transcription factor, Egr-1

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DESCRIPTION (provided by applicant): The Candidate is a young investigator dedicated to developing an academic research career focused on the identification and characterization of molecular mechanisms which contribute to ethanol-induced liver injury. The candidate has a strong background in innate immunology and has developed a particular expertise in the use of different mouse models that recapitulate hepatic steatosis, hepatitis and fibrosis to test specific hypotheses involved in development of liver injury. Use of these model systems has revealed an important role for the transcription factor Egr-1 in each of these systems. The Candidate's recent and current work has provided her with the opportunity to develop her own research program and begin her transition to independence. The Career Development plan described in this application outlines 2-years of mentored training which includes technical skills training in addition to career development activities designed to promote the successful transition to independence. A 3-year program of independent scientific and career development after successful recruitment as an Assistant Professor position to a competitive academic research institution is also outlined. The Candidate's Mentor has a proven track-record of excellent scientific productivity and successful mentorship and can provide the Candidate with a solid research environment in her laboratory at the Lerner Research Institute at the Cleveland Clinic. Research plan: Ethanol-induced hepatic fibrosis is a severe form of liver disease. Although great strides have been made in understanding the mechanisms by which fibrosis is induced and how it resolves, these discoveries have not yet lead to improved therapeutic strategies. Egr-1 is a transcription factor that regulates a broad array of genes involved in inflammation and in the wound healing response. Our published studies demonstrate that Egr-1 is a critical modulator of ethanol-induced fatty liver and acute hepatic inflammation in mice. Due to the ability of Egr-1 to regulate genes that are modulators of fibrosis, we hypothesize that Egr-1 will be an important contributor to fibrotic disease in the liver. Our preliminary data reveal that, in egr-1-/- mice, CCI4- induced liver injury and fibrosis are enhanced, suggesting previously unknown, novel biological roles for Egr- 1 in fibrosis. In three specific aims, we will characterize the hepatic pathology in egr-1-/- mice after CCI4 exposure alone and in mice exposed to chronic ethanol and CCI4, focusing on the biology of hepatic stellate cells. We expect that the results from these studies will reveal previously unrecognized roles of Egr-1 in hepatic fibrosis and hepatic stellate cell biology. Public Health Relevance: Hepatic fibrosis, or scarring of the liver, is a significant health problem in the United States. Regardless of the agent responsible for hepatic fibrosis, the outcome is the same; patients with fibrotic livers are likely to progress to cirrhosis and succumb due to liver failure. Currently, liver transplantation is the only cure for end stage liver disease. Our studies will contribute to our understanding of fibrosis and help to define new ways to can heal fibrotic lesions in the liver.