Role of Aldose Reductase-Like-1 in Colon Tumorigenesis

醛糖还原酶样 1 在结肠肿瘤发生中的作用

• 批准号: 7386970
• 负责人: Deliang Cao
• 金额: $ 16.37万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-03 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7386970
• 关键词: 2-butenal; 4 hydroxynonenal; Accounting; Acrolein; Address; Affect; Alcohols; Aldehyde Reductase; American; Cancer Etiology; Cells; Cessation of life; Chemoprevention; Chronic; Colon; Colon Carcinoma; Colorectal Cancer; Condition; Crohn' s disease; Cultured Cells; DNA Damage; DNA Sequence; Daily; Data; Detection; Development; Diacetyl; Diagnosis; Diet; Disease; Dysplasia; Early Diagnosis; Environment; Epigenetic Process; Funding; Future; Gene Mutation; Gene Targeting; Gene Transfer; Genes; Genetic; Genus Cola; Human; Immunohistochemistry; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Intestines; Laboratories; Left colon; Lesion; Lipid Peroxidation; Malignant - descriptor; Malignant Neoplasms; Messenger RNA; Metabolism; Pathogenesis; Patients; Prevention; Proteins; Pyruvaldehyde; Range; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; Role; Sequence Analysis; Specimen; Testing; Tetracycline; Tetracyclines; Time; Tissues; Toxic effect; Toxin; Tumor Tissue; Ulcerative Colitis; United States; Western Blotting; colorectal cancer prevention; cytotoxic; functional status; improved; interest; neoplastic; novel; pathogen; prevent; response; trans-2-hexenal; tumorigenesis

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）： 该 R21 重新提交详细介绍了一项关于醛糖还原酶样 1 (ARL-1) 在预防反应性羰基诱导的结肠慢性炎症和恶性肿瘤中的作用的探索性研究。在美国，结直肠癌每年诊断出超过 106,680 例新病例，导致超过 55,000 人死亡，这表明需要改进这种疾病的预防、检测和治疗。慢性炎症性肠病（溃疡性和克罗恩病）影响着多达 200 万美国人，与结直肠癌的发生有关。亲电羰基化合物遍布于我们的日常环境和各种饮食中，并在细胞代谢过程中不断产生，是肠道炎症和肿瘤发生的重要病原体。 ARL-1 是一种在正常结肠中特异性表达的新型蛋白质，对反应性羰基表现出强大的酶活性，保护细胞免受羰基损伤。特别有趣的是，我们实验室的初步数据表明，ARL-1 蛋白在测试的炎症和恶性结肠组织中丢失。因此，我们假设 ARL-1 可能会阻止结肠细胞免受饮食反应性羰基的影响，从而保护它们免受羰基损伤。通过遗传或表观遗传因素导致的 ARL-1 缺失可能会使结肠细胞容易受到羰基毒素的影响，从而导致炎症和肿瘤病变。这项探索性研究将解决以下问题：ARL-1 在调节细胞对反应性羰基反应，特别是在 DNA 损伤中的作用是什么？恶性结肠组织中ARL-1的表达水平是多少？ ARL-1 表达与结肠癌的类型、分级和分化有何相关性？炎症性结肠组织和癌症前体组织（例如不典型增生）中 ARL-1 的表达水平是多少？ 我们将通过以下具体目标来回答这些问题：（1）使用ARL-1基因靶向细胞确定ARL-1活性对亲电子羰基诱导的DNA损伤的影响，以及（2）评估ARL-1的表达和功能使用实时逆转录酶聚合酶链反应、蛋白质印迹、免疫组织化学和 ARL-1 酶活性/基因测序分析，检测炎症和恶性结肠组织中的 1 基因。由此产生的数据将定义 ARL-1 在保护细胞免受反应性羰基损伤中的作用，并验证 ARL-1 作为预防结肠癌的新靶点。成功的研究结果将支持未来广泛的 R01 研究，通过改进结肠癌的化学预防、早期诊断和治疗使慢性炎症患者受益。7。项目叙述 慢性炎症性肠病（溃疡病和克罗恩病）与结肠癌密切相关，结肠癌是美国癌症死亡的第二大原因。存在于饮食中或在细胞代谢过程中产生的亲电羰基是炎症和肿瘤性肠病的重要病原体。拟议的研究将阐明一种新型蛋白质 ARL-1 在保护结肠细胞免受羰基损伤中的作用，验证 ARL-1 作为预防结肠癌的新靶点。