This R21 resubmission details an exploratory study on the role of aldose reductase-like-1 (ARL-1) in preventing reactive carbonyl-induced chronic inflammation and malignancy in the colon. With greater than 106,680 new cases diagnosed annually, colorectal cancer accounts for more than 55,000 deaths each year in the United States, indicating a need for improved prevention, detection, and treatment of this disease. Chronic inflammatory bowel diseases (ulcerative and Crohn's disease), affecting up to two million Americans, is associated with the development of colorectal cancer. Electrophilic carbonyls pervade our daily environment and various diets and are produced constantly during cellular metabolism, being important pathogens of intestinal inflammation and tumorigenesis. ARL-1, a novel protein with specific expression in the normal colon, displays strong enzymatic activity toward reactive carbonyls, protecting cells from carbonyl lesions. Of particular interest, preliminary data from our laboratory indicates that ARL-1 protein is lost in tested inflammatory and malignant colon tissues. Therefore, we hypothesize that ARL-1 may block colon cells from dietary reactive carbonyls, protecting them from carbonyl lesions. The loss of ARL-1, via genetic or epigenetic factors, may leave colon cells vulnerable to carbonyl toxins, resulting in inflammatory and neoplastic lesions. This exploratory study will address the following questions: What is the role of ARL-1 in regulating cellular response to reactive carbonyls, particularly in DNA damage? What is the level of ARL-1 expression in malignant colon tissues? How does ARL-1 expression correlate with the type, grade, and differentiation of colon cancer? What is the level of ARL-1 expression in inflammatory colon tissues and cancer precursors, such as dysplasia? We will answer these questions through the following specific aims: (1) determine the effect of ARL-1 activity on DNA damage induced by electrophilic carbonyls, using ARL-1 gene targeted cells, and (2) evaluate the expression and function of ARL-1 gene in inflammatory and malignant colon tissues using real time reverse transcriptase polymerase chain reaction, Western blot, immunohistochemistry, and ARL-1 enzymatic activity/gene sequencing analysis. The resulting data will define the role of ARL-1 in protecting cells against reactive carbonyl lesions and validate ARL-1 as a novel target for prevention of colon cancer. Successful study results will support an extensive R01 study in the future, benefiting chronic inflammatory patients through improved chemoprevention, early diagnosis, and treatment of colon cancer.7. Project Narrative Chronic inflammatory bowel diseases (ulcerative and Crohn's disease) are strongly associated with colon cancer - the second leading cause of cancer deaths in the United States. Electrophilic carbonyls, present in diet or produced during cellular metabolism, are important pathogens of inflammatory and neoplastic bowel diseases. The proposed study will elucidate the role of a novel protein, ARL-1, in protecting colon cells from carbonyl lesions, validating ARL-1 as a novel target for the prevention of colon cancer.
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