Project Summary
Alcohol-associated liver disease (ALD) is responsible for nearly half of all deaths from liver disease. Despite
the severity of this disease, there remain no FDA-approved treatments for any stage of the disease,
highlighting the critical need to elucidate the underlying mechanisms of ALD progression to develop new
therapies. Mitogen-activated protein kinase phosphatase 1 (MKP-1) is the archetypal member of the dual-
specificity phosphatases with a pivotal role in organ inflammation and injury, including in the liver. Earlier work
showed that decreased MKP-1 levels are associated with the activation of c-Jun N-terminal kinase (JNK),
which triggers an apoptotic cascade leading to alcohol induced liver injury. However, the exact mechanisms of
how MKP-1 downregulation leads to hepatocyte injury and/or inflammation in ALD are known. Moreover, the
role of MKP-1 in macrophages and MAPK-driven inflammation in ALD has never been examined. Our
preliminary studies show that MKP-1 deletion in hepatocytes augments alcohol-induced liver injury is a NIAAA
chronic plus binge model of ALD. Data also suggest that MKP-1 deletion in hepatocytes sensitizes them to
TNFα induced toxicity. As an aspiring scientist whose goal is to pursue a career in alcohol-related multi-organ
pathology, investigating new players in ALD pathogenesis 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 mentors Dr. Gobejishvili (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 the role of
alcohol-associated downregulation of MKP-1 in the pathogenesis of ALD. The first aim of this study is to further
characterize the role of MKP-1 deletion in hepatocytes using hepatocyte specific MKP-1 knpockout mice in two
different mouse models of ALD. I will isolate hepatocytes and immune cells from these models, examine the
effect of MKP-1 deletion on pro-inflammatory chemokine production and immune cell phenotype and describe
changes in hepatocyte and immune cell health and function. The second aim will determine the role of MKP-1
specifically in macrophages using RAW 264.7 macrophage cell line, primary Kupffer cells and macrophage-
specific knockout mice. To complete this research, I will follow a detailed training plan laid out for me by my co-
mentors and pursue my career goals. 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. 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.