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

基本信息

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
项目类别：
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&apos 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

项目摘要

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）：高级糖化终产物（AGE）是通过脂质、蛋白质和核酸的非酶糖化形成的一组异质化合物。 AGEs 是在正常新陈代谢过程中内源性形成的，而 AGEs 则由高温加工食品和吸烟过程中外源性形成。 N5-（羧甲基）-赖氨酸（CML）-AGE 是特征最明确的 AGE 之一。高血糖情况下，人体组织中 AGE 的积累会加速。 AGE 通过与 AGE 受体 (RAGE) 相互作用引发氧化应激和炎症。可溶性 RAGE (sRAGE) 中和 RAGE 介导的反应，因此可作为抗炎因子。我们最近报道，sRAGE 水平显着预测芬兰男性吸烟者患结直肠癌 (CRC) 的风险较低。 AGE 和 sRAGE 在 CRC 发展中的作用尚未在女性中进行研究。我们假设 AGE 有助于 CRC 的发展，而 sRAGE 则发挥保护作用。我们提出了一项病例队列研究，该研究以 NIH 资助的三项研究为基础，这些研究是在妇女健康倡议 (WHI) 观察性研究中对 93,676 名绝经后妇女进行的队列研究。拟议的研究包括 425 例 CRC 病例和 791 名随机选择的子队列参与者。该研究有三个具体目的： 1) 检查 CML-AGE、sRAGE 的基线空腹循环水平以及 sRAGE/CML 比率与随后发生 CRC 的风险之间的关联； 2) 检查亚队列参与者中 CML-AGE 和 sRAGE 循环水平的独立预测因素，包括年龄、体重指数、饮酒、每日平均营养素摄入量（例如碳水化合物营养素和脂肪酸）和吸烟； 3）探讨CML-AGE、sRAGE的循环水平以及胰岛素抵抗、炎症和雌二醇的血清学标志物与结直肠癌风险之间的相互关系。预诊断生物样本和暴露信息以及之前测量的分析物的可用性使得这项研究高度可行和高效。这项研究的长期目标是阐明一个可修改的途径，AGEs/RAGE，它可能将环境暴露（例如饮食摄入）、炎症和胰岛素抵抗与 CRC 病因和预后联系起来。公共卫生相关性：尚未在女性中研究 AGEs/RAGE 轴在 CRC 发展中的重要性。这项研究的结果可能有助于识别结直肠癌潜在可改变的危险因素和监测疾病进展的生物标志物。公共卫生相关性：晚期糖基化终产物 (AGE) 是在高血糖条件下形成和积累的蛋白质糖加合物。 AGE 与 AGE 受体 (RAGE) 的结合会促进氧化应激和炎症，而可溶性 RAGE 可以阻止这种效应。本申请旨在研究女性健康倡议观察研究中 AGE 是否会增加结直肠癌风险，以及可溶性 RAGE 是否在绝经后妇女结直肠癌的发展中发挥保护作用。