The goal of this research proposal is to determine the role of Phosphatase of Regenerating Liver-3 (also known as PRL-3) in the biological response to alcohol exposure and toxicity. The PRL family of enzymes has become widely studied due to their potential roles in cancer and malignant disease, yet little is known and their function and regulation in vivo. Strong evidence indicates that PRL-3 is a mediator of several phenotypes elicited by ethanol exposure such as enhanced intestinal cell proliferation, angiogenesis, and cancers of the upper and lower digestive tract. These observations combined with our preliminary studies have indicated that there is a potential role for PRL-3 in mediating the phenotypes of alcohol exposure as well as alcohol-induced colorectal cancer. To study the role of PRL-3 in ethanol action, I have created a novel gene-targeted animal model can produce global and tissue-specific PRL-3 knockout mice. Using the knockout mouse model, the contribution of PRL-3 to alcohol-induced intestinal damage and alcohol-induced colorectal cancer will be assessed. These studies will ultimately lead to a better understanding of a gene potentially involved in the biological response to alcohol exposure as well as a potentially validating PRL-3 as a therapeutic target for the treatment of alcohol-induced colorectal cancer. PUBLIC HEALTH RELEVANCE: There is an enormous need to understand and treat the causes of alcohol-related diseases, particularly those that affect the gastrointestinal tract. Phosphatase of Regenerating Liver-3 is a gene associated with many of the phenotypes of alcohol exposure such as intestinal damage and alcohol-induced colorectal cancer. The studies proposed here represent an innovative approach to understanding a potentially important target for the treatment of alcohol-associated diseases.