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重新提出详细介绍了一项探索性研究，该研究涉及醛糖还原酶样-1（ARL-1）在防止反应性羰基诱导的慢性炎症和结肠恶性肿瘤中的作用。每年被诊断出106,680例新病例，在美国，大肠癌每年造成55,000多人死亡，这表明需要改善预防，检测和治疗该疾病。影响多达200万美国人的慢性炎症性肠病（溃疡性和克罗恩病）与结直肠癌的发展有关。亲电羰基遍布我们的日常环境和各种饮食，并在细胞代谢过程中不断产生，是肠炎和肿瘤发生的重要病原体。 ARL-1是一种在正常结肠中具有特异性表达的新型蛋白质，它表现出对反应性羰基的强酶活性，可保护细胞免受羰基病变的影响。特别有趣的是，我们实验室的初步数据表明，在测试的炎症性和恶性结肠组织中，ARL-1蛋白会丢失。因此，我们假设ARL-1可能会阻止结肠细胞从饮食中的反应性羰基上，从而保护它们免受羰基损伤。通过遗传或表观遗传因子的ARL-1丧失可能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的反应中的作用是什么，特别是在DNA损伤中？恶性结肠组织中ARL-1表达的水平是多少？ ARL-1表达与结肠癌的类型，等级和分化有何关系？炎性结肠组织和癌症前体（例如发育不全）中ARL-1表达的水平是多少？ 我们将通过以下具体目的回答这些问题：（1）使用ARL-1基因靶向细胞确定ARL-1活性对由亲电羰基诱导的DNA损伤的影响，以及（2）使用实时反向转录酶氧化酶氧化酶，不含培养基 - 培训，培训，培训，培训，不合时宜地，不逆转录酶，评估ARL-1基因在炎症和恶性结肠组织中的表达和功能测序分析。所得数据将定义ARL-1在保护细胞免受反应性羰基病变中的作用，并验证ARL-1作为预防结肠癌的新靶标。成功的研究结果将在未来提供广泛的R01研究，从而通过改善化学预防，早期诊断和结肠癌治疗来使慢性炎症患者受益。7。项目叙述 慢性炎症性肠病（溃疡性和克罗恩病）与结肠癌密切相关，这是美国癌症死亡的第二大原因。饮食中存在或在细胞代谢过程中产生的亲电羰基是炎症和肿瘤肠道疾病的重要病原体。拟议的研究将阐明一种新型蛋白ARL-1在保护结肠细胞免受羰基病变中的作用，从而验证ARL-1是预防结肠癌的新靶标。