sEH Inhibition in Alcoholic Liver Disease: A Novel Therapeutic Strategy

项目总结

Project Summary Alcoholic liver disease (ALD) is the most common liver disease and is responsible for nearly half of all deaths from diseases affecting this organ. Despite this, there remain no FDA-approved treatments for any stage of the disease, highlighting the need for the discovery of new therapies. As an aspiring scientist whose goal is to pursue a career in alcohol-related multi-organ pathology, investigating new therapies for ALD treatment would not only help fill this medical need but also serve as an excellent platform from which to learn how to become a successful scientist. With the help and supervision of my co-mentors Dr. Kirpich (an expert in basic research on ALD) and Dr. McClain (an expert on clinical aspects of the disease) as well as several knowledgeable collaborators, I will investigate soluble epoxide hydrolase (sEH) inhibition as a novel therapeutic strategy for the treatment of ALD using pre-clinical mouse models. This approach has been applied to other inflammatory diseases, but not to ALD, a disease shown by previous work in our group to be characterized by a loss of anti-inflammatory epoxygenated lipids (epoxides), in part due to their rapid degradation by sEH. I have generated substantial preliminary data with an orally-administered sEH inhibitor in a chronic-binge mouse model of ALD that recapitulates human ALD. Through two related, but independent, specific aims proposed in this application I will further assess the efficacy of sEH inhibition and explore its mechanisms of action. Aim 1 will use pharmacological and genetic ablation of sEH to further characterize the effects of sEH inhibition in mouse models of ALD. Aim 2 will describe the mechanistic effects of individual anti-inflammatory epoxides on changes in hepatocyte and immune cell health and function to explain changes seen in vivo. To complete this research, I will follow a detailed training plan laid out for me by my co-mentors and pursue the career goals that I have set for myself. These include, among others, continuing my didactic training in areas relevant to my research, gaining experience in new laboratory techniques, developing effective written and oral communication skills, and building a professional network of scientists. For example, to assess liver injury and changes in cellular function I will learn to read histological liver slides, use enzymatic assays, set up ELISAs, isolate and culture primary hepatocytes and macrophages, and learn flow cytometry. The research environment at the University of Louisville’s state-of- the-art Clinical and Translational Research Building is highly productive and staffed with expert faculty and research personnel willing to help me learn these techniques and advise me as I pursue my training and career goals. My academic department, the Department of Pharmacology & Toxicology, is equally positioned to support my training in the classroom and provide many resources (e.g. travel funds, career development seminars, and new courses) to ensure my success. Collectively, the training and research proposed here will not only fill a significant need for the development of ALD treatments, but will also foster my development from a young scientist to a successful, independent investigator in the field of alcohol-induced organ disease.