Uncovering Roles of Metabolites in Colorectal Cancer Etiology

揭示代谢物在结直肠癌病因学中的作用

• 批准号: 10224955
• 负责人: Xiang Shu
• 金额: $ 38.99万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224955
• 关键词: Affect; Asia; Asians; Award; Biological; Biological Markers; Blood; Blood specimen; Body mass index; Branched-Chain Amino Acids; Cancer Biology; Cancer Etiology; Clinical; Cohort Studies; Collaborations; Colorectal; Colorectal Cancer; Communities; Data; Databases; Development; Diagnosis; Diagnostic; Dietary intake; Disease; Dyslipidemias; Energy Metabolism; Etiology; European; Framingham Heart Study; Genetic; Genetic Predisposition to Disease; Genotype; Goals; Healthy Eating; Homeostasis; Intake; Investigation; K-Series Research Career Programs; Knowledge; Life Style; Link; Liquid Chromatography; Malignant Neoplasms; Malignant neoplasm of pancreas; Measurement; Measures; Meat; Mediation; Mediator of activation protein; Mentors; Metabolic; Metabolic Diseases; Metabolism; Modeling; Molecular Epidemiology of Cancer; Molecular Genetics; Nested Case-Control Study; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Observational Study; Parents; Participant; Pathway interactions; Phase; Physical activity; Pilot Projects; Plasma; Play; Population Genetics; Predisposition; Prevention; Prospective Studies; Research; Research Personnel; Risk; Risk Assessment; Risk Factors; Role; Sample Size; Susceptibility Gene; Techniques; Time; Training; Translating; United States; Vegetables; Waist-Hip Ratio; Woman; base; cancer biomarkers; cancer diagnosis; cancer initiation; cancer risk; career; case control; colorectal cancer prevention; colorectal cancer risk; cost; cost efficient; density; design; genetic epidemiology; genetic predictors; genetic variant; genome wide association study; genome-wide; genomic locus; good diet; high throughput technology; improved; in silico; indexing; innovation; instrument; lifestyle factors; male health; meetings; metabolome; metabolomics; novel; novel marker; offspring; physical inactivity; potential biomarker; predictive modeling; prevent; prospective; risk stratification; screening; tandem mass spectrometry; tool; tumor metabolism; tumor progression

PROJECT SUMMARY Metabolic perturbation or reprogramming is considered one of the hallmarks of cancer. Several common metabolic disorders, such as obesity, type 2 diabetes, and dyslipidemia, have been linked to colorectal cancer (CRC) risk. With the advances in the techniques of metabolomics, hundreds to thousands of metabolites can be systematically measured in an agnostic manner. For a well-designed prospective metabolomic study of cancer, the identification of novel risk-associated biomarkers will shed new lights on the cancer etiology and related biological pathways. Conventional studies evaluating metabolites are costly and may suffer from biases commonly encountered in the observational studies. It has been increasingly recognized that genetic factors play a significant role in determining the levels of many metabolites. Herein, I propose a cost-efficient approach to systematically evaluate the associations between plasma levels of metabolites and CRC risk. I also incorporate didactic training on molecular/genetic epidemiology, causal inference, cancer biology and metabolism, and population genetics in this application to accomplish my research and career goals described below. The proposed research is composed of four aims. In aim 1, I will build models to predict metabolite levels using existing metabolomics and high-density genotyping data from a public database and possible data generated at Vanderbilt. In aim 2, metabolites with satisfactory prediction accuracy and meeting other criteria will be evaluated in three large-scale CRC consortia with a combined sample size of ~80,900 cases and 115,000 controls to assess the associations of genetically predicted metabolite levels with CRC risk. In collaboration with other investigators during the R00 phase of this award, I will then conduct a nested case- control study to confirm up to ten metabolites identified from in silico analysis by direct measurement of these metabolites using pre-diagnosis plasma collected in three large cohort studies (aim 3). Finally, I will evaluate the potential mediation effects of metabolites for the associations between lifestyle factors including obesity (body mass index and waist-hip-ratio), physical activity, red meat intakes, vegetable intakes, healthy eating index and CRC risk (aim 4). This innovative study will, for the first time, systematically search for novel metabolite biomarkers for CRC risk using genetic instruments and validate the identified associations by direct measurement. In addition, this study will expand the understanding of underlying mechanisms causing CRC. The proposed career development award will help me building advanced knowledge of genetic and molecular epidemiology, cancer metabolism, and CRC etiology and risk assessment to transition to a successful independent investigator.

项目摘要 代谢紊乱或重编程被认为是癌症的标志之一。几种常见 代谢紊乱，如肥胖、2型糖尿病和血脂异常，与结直肠癌有关 (CRC)风险随着代谢组学技术的发展， 以一种不可知论的方式进行系统的测量。对于一项设计良好的前瞻性代谢组学研究， 新的风险相关生物标志物的鉴定将为癌症病因学提供新的线索， 相关的生物学途径。传统的研究评估代谢物是昂贵的，并可能遭受偏见 这在观察性研究中很常见。人们越来越认识到，遗传因素 在确定许多代谢物的水平中起重要作用。在此，我提出了一个具有成本效益的方法， 系统评价血浆代谢物水平与结直肠癌风险之间的关系。我也 纳入分子/遗传流行病学、因果推断、癌症生物学和 代谢和群体遗传学在此应用程序中完成我的研究和职业目标描述 下面本研究主要有四个目的。在目标1中，我将建立模型来预测代谢物 使用公共数据库中现有的代谢组学和高密度基因分型数据以及可能的数据 在范德比尔特生产的。在目标2中，具有令人满意的预测准确性并满足其他标准的代谢物 将在三个大规模CRC联盟中进行评估，合并样本量约为80，900例， 115，000对照，以评估遗传预测代谢物水平与CRC风险的相关性。在 在本奖项的R 00阶段，我将与其他研究人员合作，然后进行嵌套案例- 对照研究，通过直接测量这些代谢物，确认从计算机模拟分析中鉴别出的多达10种代谢物 使用在三个大型队列研究中收集的诊断前血浆的代谢物（AIM 3）。最后，我将评估 代谢物对包括肥胖在内的生活方式因素之间的关联的潜在中介作用 (body体重指数和腰臀比），体力活动，红肉摄入量，蔬菜摄入量，健康饮食 指数和CRC风险（目标4）。这一创新性的研究将第一次系统地寻找小说 使用遗传工具评估CRC风险的代谢物生物标志物，并通过直接 测量.此外，这项研究将扩大对导致CRC的潜在机制的理解。 拟议的职业发展奖将帮助我建立先进的知识，遗传和分子 流行病学，癌症代谢，CRC病因和风险评估，以过渡到一个成功的 独立调查员