Metabolomic signatures of inflammation and metabolic health in relation to colorectal cancer risk

项目总结/摘要 结直肠癌（CRC）是男性和女性中第三大常见癌症。炎症的作用 和代谢紊乱在CRC发病机制中的作用已得到证实。然而，生物 这些途径的潜在机制以及它们如何介导饮食-CRC联系尚不清楚。 在这个应用中，我们提出了衍生代谢组学特征，表征炎症和代谢， 在三个大的队列健康：护士健康研究I和II和卫生专业人员随访研究。我们 将使用降秩回归，这是一种新的统计方法，结合了数据驱动的方法， 主成分分析与先验知识的中间因素，以确定模式的代谢产物 描述了表征1）炎症（TNF受体）的生物标志物和生活方式因素的最大变化 超家族成员1B、白细胞介素6、C-反应蛋白和脂联素）和2）代谢健康（体重 指数、腰围、C肽、体力活动和脂联素）。然后我们将使用弹性网 回归以选择对使用降秩推导的两个因子有贡献的最重要代谢物 回归并测试这些代谢组学特征与CRC风险之间的关联， 作为加工肉类消费的媒介。这个项目的目标是阐明生物学 炎症和代谢健康与CRC相关的机制，并在长期内，制定策略， 优化饮食和生活方式干预以预防CRC。贝弗女士（PI）将在以下条件下开展本研究 哈佛T.H.流行病学和营养学教授Meir Stampfer博士的指导。禅宗 公共卫生（HSPH）;宋明阳博士，临床流行病学和营养学助理教授， Jeffrey Meyerhardt博士，一位执业胃肠道肿瘤学家和达纳法伯研究所的研究员。 哈佛医学院（HMS）癌症研究所和医学教授;梁黎明博士，助理 HSPH统计遗传学教授;爱德华·乔万努奇博士，流行病学和营养学教授， HSPH; Andrew Chan博士，执业胃肠道肿瘤学家和癌症流行病学主任， 马萨诸塞州总医院;魏征博士，医学教授和副主任， 范德比尔特大学医学中心人口科学研究。贝弗女士是一个不断上升的第四年 哈佛/麻省理工学院医学博士项目的学生，即将开始她的人口健康的第二年 科学博士课程在HSPH。她的培训计划包括高级生物统计学课程， 流行病学方法，地方研讨会和全国会议，以及每周与导师的会议。的 培训计划旨在支持贝弗女士成为一名流行病学医生的长期目标 在癌症风险因素方面有专业知识该计划包括在贝弗女士 在医学院的最后两年里，她接受了博士前培训，并继续有机会进行研究。

Project Summary/Abstract Colorectal cancer (CRC) is the third most common cancer in both men and women. The role of inflammation and metabolic disturbance in the pathogenesis of CRC is well-established. However, the biological mechanisms underlying these pathways and how they may mediate the diet-CRC link are poorly understood. In this application, we propose to derive metabolomic signatures that characterize inflammation and metabolic health in three large cohorts: the Nurses’ Health Study I and II and Health Professionals Follow-up Study. We will use reduced rank regression, a novel statistical method that combines the data-driven approach of principal components analysis with prior knowledge of intermediate factors, to identify patterns of metabolites describing maximal variation in biomarkers and lifestyle factors that characterize 1) inflammation (TNF receptor superfamily member 1B, interleukin 6, C-reactive protein, and adiponectin) and 2) metabolic health (body mass index, waist circumference, C-peptide, physical activity, and adiponectin). We will then use elastic net regression to select the most important metabolites contributing to the two factors derived using reduced rank regression and test the association between these metabolomic signatures and CRC risk, independently and as a mediator of processed meat consumption. The goal of this project is to elucidate the biological mechanisms relating inflammation and metabolic health to CRC and, in the long-term, to generate strategies to optimize dietary and lifestyle interventions for CRC prevention. Ms. Bever (PI) will conduct this research under the mentorship of Dr. Meir Stampfer, Professor of Epidemiology and Nutrition at Harvard T.H. Chan School of Public Health (HSPH); Dr. Mingyang Song, Assistant Professor of Clinical Epidemiology and Nutrition at HSPH; Dr. Jeffrey Meyerhardt, a practicing gastrointestinal oncologist and researcher at the Dana-Farber Cancer Institute and Professor of Medicine at Harvard Medical School (HMS); Dr. Liming Liang, Associate Professor of Statistical Genetics at HSPH; Dr. Edward Giovannucci, Professor of Epidemiology and Nutrition at HSPH; Dr. Andrew Chan, a practicing gastrointestinal oncologist and Director of Cancer Epidemiology at Massachusetts General Hospital; and Dr. Wei Zheng, Professor of Medicine and Associate Director for Population Sciences Research at Vanderbilt University Medical Center. Ms. Bever is a rising fourth-year student in the Harvard/MIT MD-PhD Program, about to begin her second year of the Population Health Sciences PhD program at HSPH. Her training plan includes coursework in advanced biostatistics and epidemiologic methods, local seminars and national conferences, and weekly meetings with mentors. The training plan has been designed to support Ms. Bever’s long-term goal of becoming a physician-epidemiologist with expertise in risk factors for cancer. The plan includes integration of clinical activities during Ms. Bever’s pre-doctoral training and continued opportunities for research during her last two years of medical school.