Human and Bacterial Molecular Pathways in Cancer Risk: Modulation by Diet

人类和细菌癌症风险的分子途径：饮食调节

• 批准号: 9187871
• 负责人: JOHANNA W LAMPE
• 金额: $ 70.99万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9187871
• 关键词: Address; Affect; Animal Model; Antibodies; Apoptosis; Attention; Biological Markers; Biometry; Blood; C-reactive protein; Carbohydrates; Cell physiology; Cereals; Characteristics; Complex; Crossover Design; DNA Repair; Data; Diet; Dietary Fiber; Dietary Intervention; Dietary Practices; Endotoxins; Experimental Nutrition; Fabaceae; Fasting; Feces; Food; Genes; Glycemic Index; Human; Individual; Inflammation; Insulin-Like Growth Factor I; Intake; Link; Macronutrients Nutrition; Malignant Neoplasms; Measurement; Measures; Mediating; Metabolism; Metagenomics; Molecular; Nutrient; Nutritional Study; Obesity; Observational Study; Overweight; Participant; Pathway interactions; Pattern; Phenotype; Plasma; Play; Predisposition; Proteins; Proteome; Proteomics; Public Health; Randomized; Recommendation; Regulatory Pathway; Reporting; Research Personnel; Ribosomal RNA; Risk; Role; Sampling; Satiation; Signal Transduction; Source; Specimen; Standardization; Statistical Methods; Statistical Models; Technology; Testing; Thinness; Variant; Weight; Xenobiotic Metabolism; cancer biomarkers; cancer prevention; cancer risk; cancer therapy; cancer type; carcinogenesis; design; dietary constituent; epigenomics; exposed human population; feeding; fruits and vegetables; gut microbiome; improved; inflammatory marker; insight; lipopolysaccharide-binding protein; metabolome; metabolomics; metagenome; microbial; microbial community; novel; nutrition; nutrition related genetics; nutritional genomics; pleiotropism; protein biomarkers; public health relevance; response; response biomarker; sugar; transcriptomics

 DESCRIPTION (provided by applicant): We are responding to PAR-13-375, Nutrigenetics and Nutrigenomics Approaches for Nutrition Research. This amended proposal, supported by a team of well-established investigators in proteomics, metabolomics, gut microbiome, experimental nutrition, and biostatistics, aims to evaluate effects of specific diet patterns on biomarkers of cancer-risk pathways in a controlled feeding study. Diet is a complex exposure in humans, aspects of which are recognized to play a role in the risk of several cancers. To date, the focus of experimental nutrition has been on the impact of specific nutrients or dietary constituents on mechanisms of cancer prevention or treatment, with less attention placed on the response to multiple, concurrent nutrient exposures, as would occur in free-living humans consuming food. Observational studies suggest that we also need to understand the response to dietary patterns to better target public health recommendations for cancer prevention. Dietary constituents have pleiotropic effects and modulate a variety of pathways important in carcinogenesis. Proteomics and metabolomics have the capacity to capture this range of responses. Further, the gut microbiome and gut microbial metabolites have been shown to affect some of these pathways and have been implicated in the risk of several cancers. We will use a carefully designed, well-controlled feeding study to address the following aims: 1) Compare the effects of two distinct dietary patterns fed as controlled diets on proteomic biomarkers of regulatory pathways important in cancer susceptibility; 2) Compare the effects of the two dietary patterns on (a) gut microbial community and the gut metagenome and metatranscriptome and (b) the plasma metabolome; and 3) Explore what diet-induced changes in the metatranscriptome and metabolomics profiles explain the variation in proteomic measures that also changed in response to diet. We will use data and samples from a completed randomized cross-over feeding study, Carbohydrate and Related Biomarkers (CARB), where 80 participants [40 normal weight (BMI 18.5-25.0 kg/m2) and 40 overweight to obese (BMI 28.0-40.0 kg/m2)] consumed two controlled diets for 28 days each. One diet was high in whole grains, fresh fruits and vegetables. The other substituted refined grains for whole grains, and provided carbohydrates from mostly high-glycemic index food sources. All food was provided to participants and energy content and macronutrient composition was identical in both diets. Each participant served as their own control. Fasting blood and stool were collected at the beginning and end of each diet. We will use a novel protein antibody array to measure the plasma proteome, will characterize the gut microbial community using 16S rRNA sequencing, metagenomics and metatranscriptomics, and will measure the plasma metabolome using targeted and global approaches. We will use novel statistical methods for integrating the various omics data and test for associations using state-of-the- art single-marker and pathway-enrichment statistical models which adjust for demographic variation.

 描述（由应用程序提供）：我们正在响应13-375 PAR，营养学和营养研究方法的营养研究方法。这项修订的提案得到了一支成立的蛋白质组学，代谢组学，肠道微生物组，实验营养和生物统计学的良好研究者的支持，旨在评估特定饮食模式在对照喂养研究中对癌症风险途径生物标志物的影响。饮食是人类的复杂暴露，其各个方面被认为在几种癌症的风险中发挥作用。迄今为止，实验营养的重点一直在特定营养物质或饮食构成对预防癌症或治疗机制的影响，而对多种同时养分暴露的反应较少，就像食用食物的自由生活的人一样。观察性研究表明，我们还需要了解对饮食模式的反应，以更好地针对预防癌症的公共卫生建议。饮食构成具有多效效应，并调节在癌变中重要的多种途径。蛋白质组学和代谢组学具有捕获这种反应范围的能力。此外，肠道微生物组和肠道微生物代谢产物已被证明会影响其中的某些途径，并因几种癌症的风险被浸渍。我们将使用经过精心设计的精心控制的喂养研究来解决以下目的：1）比较在癌症易感性中重要的调节途径蛋白质组学生物标志物的两种不同饮食模式的影响； 2）比较两种饮食模式对（a）肠道微生物群落以及肠道元基因组和metatranscriptomem和（b）血浆代谢组的影响； 3）探索饮食诱导的元转录组和代谢组学轮廓的变化解释了蛋白质组学措施的变化，这些变化也会因饮食而变化。我们将使用完整的随机交叉进食研究，碳水化合物和相关生物标志物（CARB）中的数据和样品，其中80名参与者[40个正常体重（BMI 18.5-25.0 kg/m2）和40次超重肥胖（BMI 28.0-40.0.0.0 kg/m2]消耗两天的饮食均可为28天28天。一种饮食含量很高，全谷物，新鲜水果和蔬菜。其他替代的精制晶粒用于全谷物，并提供了大多数高血糖指数食品来源的碳氢化物。所有食物均提供给参与者和能量含量，两种饮食中的大量营养素成分都是相同的。每个参与者都是自己的控制。在每种饮食的开始和结束时收集空腹血液和粪便。我们将使用一种新型的蛋白抗体阵列来测量血浆蛋白质组，将使用16S rRNA测序，宏基因组学和元文字组学来表征肠道微生物群落，并使用靶向和全球方法测量血浆代谢组。我们将使用新颖的统计方法来整合各种OMIC数据并使用最先进的单标记和途径 - 增强统计模型来进行关联测试，以调整人口统计学变化。