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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31AA019597-02
Application #
8308180
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Radaeva, Svetlana
Project Start
2011-08-01
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
2
Fiscal Year
2012
Total Cost
$42,232
Indirect Cost
Name
University of Pittsburgh
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Zimmerman, Mark W; McQueeney, Kelley E; Isenberg, Jeffrey S et al. (2014) Protein-tyrosine phosphatase 4A3 (PTP4A3) promotes vascular endothelial growth factor signaling and enables endothelial cell motility. J Biol Chem 289:5904-13
Cramer, Julie M; Zimmerman, Mark W; Thompson, Tim et al. (2014) Deletion of Ptp4a3 reduces clonogenicity and tumor-initiation ability of colitis-associated cancer cells in mice. Stem Cell Res 13:164-71