EFFECT OF WESTERN DIET IN GASTROINTESTINAL CANCER BY NMR METABOLOMICS

通过 NMR 代谢组学研究西方饮食对胃肠癌的影响

• 批准号: 9974543
• 负责人: Viswanathan V Krishnan
• 金额: $ 10.5万
• 依托单位: CALIFORNIA STATE UNIVERSITY FRESNO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9974543
• 关键词: Acetates; Address; Adipose tissue; Animal Model; Animals; Apoptosis; Bifidobacterium; Bile Acids; Biological; Biological Process; Butyrates; California; Calories; Cancer Etiology; Cancer Model; Cancer and Nutrition; Cardiovascular Diseases; Cattle; Cell Proliferation; Cells; Cessation of life; Cholesterol; Chronic; Chronic Disease; Clinical; Cluster Analysis; Collaborations; Colon; Complement; Consumption; Correlation Studies; Coupled; DNA Damage; Data; Desire for food; Developed Countries; Development; Diagnostic; Diet; Dietary Fats; Early Diagnosis; Emerging Technologies; Energy Intake; Energy Metabolism; Epidemic; Etiology; Exhibits; Experimental Designs; Exposure to; Fatty acid glycerol esters; Feces; Genes; Genomic Instability; Goals; Homeostasis; Human; Hydrophobicity; Incidence; Inflammation; Inflammatory Response; Insulin Resistance; Intestinal Cancer; Intestines; Knock-out; Knockout Mice; Knowledge; Laboratories; Lead; Learning; Lipids; Liver; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Malignant neoplasm of liver; Measurement; Mentors; Metabolic syndrome; Metabolism; Metformin; Methods; Milk; Molecular; Molecular Profiling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Magnetic Resonance; Nuclear Receptors; Obesity; Oligosaccharides; Outcome; Pancreas; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phenotype; Predisposition; Prevention; Probiotics; Process; Propionates; Proteomics; Public Health; Research; Research Training; Role; Sampling; Severity of illness; Statistical Methods; Statistical Models; Testing; Universities; Volatile Fatty Acids; absorption; bariatric surgery; base; carcinogenesis; diabetic; diabetic patient; diet and cancer; disease diagnosis; experience; functional genomics; gastrointestinal; gut microbiota; gut-liver axis; innovation; liver development; member; metabolomics; microbial; microbiota; microbiota profiles; minority student; potential biomarker; prevent; receptor; sabbatical; small molecule; spectroscopic survey; student training; sugar; tissue injury; tool; training opportunity; tumor; tumor progression; western diet

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.

项目概要 胃肠道 (GI) 癌症是一个主要的公共卫生问题，是导致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。新兴观点表明 了解饮食、微生物代谢和胃肠道癌症之间的共生关系应该是 以便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、丙酸和丁酸具有抑制炎症和癌症的功能， 而其他代谢物，例如次级胆汁酸，则促进癌变。 因此，重要的是 开发更有效的方法来早期诊断该疾病过程，评估疾病严重程度，以及 预测课程。随着人们越来越关注代谢物作为与疾病最密切相关的潜在生物标志物 癌症表型，它们可以提供临床上有用的工具，并可能开辟新的诊断途径。 根据加州大学戴维斯分校休假期间获得的经验，本申请建议 使用基于 NMR 的代谢组学应用于动物模型，探索饮食对胃肠道癌症的作用。 因此， 该项目将侧重于一个特定的研究目标来检验假设： 体内发现的过量胆固醇 一个 西方饮食（高脂肪和高糖）导致长期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，我们采取 通过利用基于核磁共振（NMR）的协作策略的还原论方法 代谢组学测量与功能基因组学、蛋白质组学等其他正在进行的研究相结合 以及微生物群概况。利用 PI 在光谱方面的专业知识的最佳实验设计 提出了核磁共振方面的建议。在测试因果关系的动物模型中，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 该提案意义重大，因为它试图利用饮食来揭示饮食与胃肠道癌症之间的分子机制 在稳健的动物模型中基于核磁共振的代谢组学方法。结果可能直接影响选择 小分子药理学工具可以更好地了解人类恶性肿瘤。