Advanced glycation end products and colorectal cancer risk in women

女性晚期糖基化终产物和结直肠癌风险

• 批准号: 8049935
• 负责人: LI JIAO
• 金额: $ 9.84万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8049935
• 关键词: Advanced Glycosylation End Products; Age; Alcohol consumption; Aldehydes; Amino Acids; Anti-Inflammatory Agents; Anti-inflammatory; Beta Carotene; Binding; Biological; Biological Markers; Body mass index; Cancer Etiology; Carbohydrates; Clinical Trials; Cohort Studies; Colorectal Cancer; Data; Development; Diagnostic; Dietary intake; Disease Progression; Environmental Exposure; Epidemiologic Studies; Epidemiology; Estradiol; Estrogens; Etiology; Event; Fasting; Fatty Acids; Food Processing; Funding; Glucose; Goals; High temperature of physical object; Hyperglycemia; Inflammation; Insulin Resistance; Insulin-Like Growth Factor I; Intake; Ketones; Lead; Leptin; Lipids; Lysine; Measures; Mediating; Metabolism; Monitor; Nucleic Acids; Nutrient; Observational Study; Odds Ratio; Oxidative Stress; Participant; Pathway interactions; Postmenopause; Proteins; Reaction; Reporting; Research; Risk; Risk Factors; Role; Signal Pathway; Smoker; Smoking; Source; Specimen; Tobacco smoke; Tobacco smoking; United States National Institutes of Health; Woman; Women' s Health; alpha Tocopherol; amino group; cancer prevention; cancer risk; cohort; design; follow-up; food consumption; glycation; high risk; human tissue; male; modifiable risk; novel; outcome forecast; oxidation; protective effect; receptor; receptor for advanced glycation endproducts; serological marker; sugar; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Advanced Glycation End-products (AGEs) are a heterogeneous group of compounds formed via the nonenzymatic glycation of lipids, proteins and nucleic acids. AGEs form endogenously during normal metabolism, and exogenously from foods processed at a high temperatures and tobacco smoking. N5- (carboxymethyl)-lysine (CML)-AGE is one of the best characterized AGEs. The accumulation of AGEs in the human tissues accelerates under hyperglycemia. AGEs trigger oxidative stress and inflammation by interacting with the receptor for AGEs (RAGE). Soluble RAGE (sRAGE) neutralizes the reactions mediated by the RAGE and therefore, acts as an anti-inflammatory factor. We recently reported that levels of sRAGE significantly predicted a lower risk of colorectal cancer (CRC) in Finnish male smokers. The role of AGEs and sRAGE in CRC development has not been investigated in women. We hypothesize that AGEs contributes to CRC development while sRAGE exerts a protective effect. We propose a case-cohort study that builds upon three NIH-funded studies conducted within the Women's Health Initiative (WHI) Observational Study of a cohort 93,676 postmenopausal women. The proposed study includes 425 incident CRC cases and 791 randomly selected subcohort participants. The study has three specific aims: 1) To examine the association between baseline fasting circulating levels of CML-AGE, sRAGE, and the sRAGE/CML ratio and risk of subsequent development of CRC; 2) to examine the independent predictors of circulating levels of CML-AGE and sRAGE among the subcohort participants, including age, body mass index, alcohol use, daily average intake of nutrients (e.g., carbohydrate nutrients and fatty acids), and tobacco smoking; and 3) to explore the inter-relationships among circulating levels of CML-AGE, sRAGE and serological markers of insulin resistance, inflammation and estradiol on the risk of CRC. The availability of pre-diagnostic bio-specimens and exposure information, as well as previously measured analytes, makes this study highly feasible and efficient. The long- term goal of this research is to elucidate a modifiable pathway, AGEs/RAGE, that may connect environmental exposure (e.g., dietary intake), inflammation, and insulin resistance with CRC etiology and prognosis. PUBLIC HEALTH RELEVANCE: The importance of the AGEs/RAGE axis in CRC development has not been investigated in women. The findings from this study may lead to identification of potentially modifiable risk factors for CRC and biomarkers for monitoring disease progression. PUBLIC HEALTH RELEVANCE: Advanced glycation end-products (AGEs) are sugar adducts to proteins that form and accumulate under conditions of hyperglycemia. Binding of AGEs with the receptor for AGEs (RAGE) promotes oxidative stress and inflammation and soluble RAGE can block such effects. This application sets out to examine whether AGEs increase colorectal cancer risk and soluble RAGE play a protective role in colorectal cancer development among postmenopausal women in the Women's Health Initiative Observational Study.

描述（由申请人提供）：晚期糖基化终产（年龄）是通过脂质，蛋白质和核酸的非酶糖基化形成的异质化合物组。年龄在正常代谢期间内源形成，并从高温和吸烟中加工的食物外源。 N5-（羧甲基） - 赖氨酸（CML）-Age是最佳特征年龄之一。人体组织中年龄的积累在高血糖下加速。年龄通过与年龄相互作用（愤怒）引发氧化应激和炎症。可溶性愤怒（Srage）中和愤怒介导的反应，因此充当抗炎因子。我们最近报道说，SRAGE水平显着预测芬兰男性吸烟者的结直肠癌（CRC）的风险较低。尚未在女性中研究年龄和SRAGE在CRC发展中的作用。我们假设年龄有助于CRC的发展，而SRAGE具有保护作用。我们提出了一项病例研究研究，该研究基于在妇女健康倡议（WHI）的观察性研究中进行的三项NIH资助的研究，该研究93,676个绝经后妇女。拟议的研究包括425例CRC病例和791个随机选择的亚细胞参与者。该研究具有三个具体的目的：1）检查基线禁食循环水平的CML-AGE，SRAGE和SRAGE/CML比率以及随后发生CRC的风险之间的关联； 2）检查亚幼虫参与者中CML-AGE和SRAGE循环水平的独立预测指标，包括年龄，体重指数，饮酒，每天的养分平均摄入量（例如碳水化合物营养素和脂肪酸）和烟草吸烟； 3）探索胰岛素抵抗，炎症和雌二醇的CML-AGE，SRAGE和血清学标志物的循环水平之间的相互关系与CRC风险。诊断前生物特异性和暴露信息以及先前测量的分析物的可用性使得这项研究高度可行和有效。这项研究的长期目标是阐明一种可修改的途径，年龄/愤怒，该途径可能与环境暴露（例如饮食摄入量），炎症和胰岛素抵抗有关CRC病因和预后。公共卫生相关性：尚未对妇女进行调查，年龄/愤怒轴在CRC发展中的重要性。这项研究的发现可能导致鉴定CRC和生物标志物的潜在可修改的危险因素，以监测疾病进展。 公共卫生相关性： 晚期糖基化终产物（年龄）是在高血糖条件下形成和积累的蛋白质的糖加合物。年龄与受体的结合年龄（RAGE）促进氧化应激，炎症和可溶性愤怒可以阻止这种影响。该应用程序旨在检查年龄是否增加结直肠癌的风险和可溶性愤怒在绝经后妇女的结直肠癌发展中起保护作用，这是女性健康计划的观察性研究。