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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要胃肠道（GI）癌症是一个主要的公共卫生问题，是癌症死亡的第二大原因肥胖和糖尿病患者发病率要高得多的发达国家。新兴的观点暗示了解饮食，微生物代谢和胃肠癌之间的共生关系应该是为了更好地预测和预防癌症的进展。积累的证据表明短链脂肪酸醋酸，丙酸和丁酸酯在抑制炎症和癌症中的功能，而其他代谢产物（例如次生胆汁酸）促进了致癌作用。因此，重要的是开发更有效的方法来早期诊断此疾病过程，评估疾病的严重程度和预后课程。随着对代谢物作为潜在的生物标志物的越来越关注，与它们是癌症表型，可以提供临床上有用的工具，并可能为诊断提供新的途径。根据加州大学戴维斯分校的休假年中获得的经验，此申请建议使用基于NMR的代谢组学应用于动物模型，探索饮食对胃癌的作用。因此，该项目将集中于检验假设的特定研究目标：在一个西方饮食（高脂肪和高糖）导致长期暴露于高水平的疏水有毒胆汁酸，从而有助于胃肠道癌的发展。为了解决这个更广泛的问题，我们承担了通过采用基于核磁共振（NMR）的协作策略来简化主义方法代谢组学测量与其他关于功能基因组学，蛋白质组学的正在进行的研究以及微生物群。最佳的实验设计，利用PI的专业知识提出了NMR的各个方面。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基因敲除（FXR KO）小鼠饮食以及NMR代谢组学方法的饮食。这提案很重要，因为它试图揭示使用饮食和胃肠癌之间的分子机制在健壮的动物模型中，基于NMR的代谢组方法。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。