EFFECT OF WESTERN DIET IN GASTROINTESTINAL CANCER BY NMR METABOLOMICS

项目摘要 胃肠道（GI）癌是一个主要的公共卫生问题，是癌症死亡的第二大原因， 发达国家肥胖和糖尿病患者的发病率要高得多。新出现的观点认为， 了解饮食、微生物代谢和胃肠道癌症之间的共生关系， 为了更好地预测和预防癌症进展。越来越多的证据表明 短链脂肪酸乙酸酯、丙酸酯和丁酸酯在抑制炎症和癌症中起作用， 而其它代谢物如次级胆汁酸促进致癌作用。 因此必须 开发更有效的方法来早期诊断这种疾病，评估疾病的严重程度， 简明课程。随着越来越多的关注代谢物作为潜在的生物标志物， 作为一种癌症表型，它们可以提供临床上有用的工具，并可能为诊断开辟新的途径。 根据在加州大学戴维斯分校休假期间获得的经验，本申请建议 将基于NMR的代谢组学应用于动物模型，探索饮食对GI癌的作用。 因此，委员会认为， 该项目将侧重于一个具体的研究目标，以检验这一假设： 体内发现的过量胆固醇 一 西方饮食（高脂肪和高糖）导致慢性暴露于高水平的疏水性有毒胆汁酸， 从而促进胃肠道癌症的发展。为了解决这个更广泛的问题，我们承诺 通过利用基于核磁共振（NMR）的协作策略， 代谢组学测量与其他正在进行的功能基因组学，蛋白质组学， 以及微生物群特征。一个最佳的实验设计，利用PI的光谱专业知识， 提出了核磁共振的几个方面。在一个动物模型中测试因果关系，我们建议研究 使用胆汁酸受体敲除（FXR KO）小鼠的饮食结合NMR代谢组学方法。这 这项提案意义重大，因为它试图揭示饮食与胃肠道癌症之间的分子机制， 一个基于NMR的代谢组学方法在一个强大的动物模型。结果可能直接影响选择 小分子药理学工具，以更好地了解人类恶性肿瘤。

Project Summary Gastrointestinal (GI) cancer, a major public health concern, is the second leading cause of cancer death in developed countries with a much higher incidence in obese and diabetic patients. The emerging view suggests that understanding the symbiotic relationship between diet, microbial metabolism and GI cancer should be considered in order to better predict and prevent cancer progression. Accumulating evidence suggests the short-chain fatty acids acetate, propionate and butyrate function in the suppression of inflammation and cancer, whereas other metabolites, such as secondary bile acids, promote carcinogenesis. Thus, it is important to develop more effective methods for early diagnosis of this disease process, assess disease severity, and prognosticate course. With increasing focus on metabolites as potential biomarkers with most closely related to a cancer phenotype, they can provide clinically useful tools and may open new avenues for diagnostics. Based on the experience gained during the sabbatical year at UC Davis, this application proposes to explore the role of diet on GI cancer using NMR-based metabolomics applied to the animal model. Accordingly, this project will focus on a specific research objective to test the hypothesis: the excess cholesterol found in a Western diet (high fat and high sugar) results in chronic exposure to high levels of hydrophobic toxic bile acids, and thereby contributes to the development of GI cancer. To address this broader issue, we undertake a reductionist approach by a collaborative strategy that utilizes a nuclear magnetic resonance (NMR) based metabolomic measurement in conjunction with other ongoing studies on functional genomics, proteomics, as well as the microbiota profile. An optimal experimental design that leverages the PI's expertise in spectroscopic aspects of NMR is proposed. In an animal model to test for cause-and-effect, we propose to study the role of diet using bile acid receptor knockout (FXR KO) mice coupled with an NMR metabolomics approach. This proposal is significant because it seeks to reveal the molecular mechanism between diet and GI cancer using an NMR-based metabolomic approach in a robust animal model. Outcomes may directly impact the selection of small molecule pharmacologic tools to better understand human malignancies.