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

项目摘要/摘要 结直肠癌(CRC)是男性和女性的第三大常见癌症。炎症的作用 而代谢紊乱在结直肠癌发病机制中的作用是公认的。然而，生物学上的 这些途径背后的机制以及它们如何调节饮食与结直肠癌的联系还知之甚少。 在这一应用中，我们建议获得表征炎症和代谢的代谢组特征 三大队列中的健康：护士健康研究I和II以及卫生专业人员跟踪研究。我们 将使用降阶回归，这是一种新的统计方法，它结合了数据驱动的方法 具有中间因素先验知识的主成分分析，以识别代谢物的模式 描述表征1)炎症(肿瘤坏死因子受体)的生物标志物和生活方式因素的最大变异 超家族成员1B、白介素6、C反应蛋白和脂联素)和2)代谢健康(身体质量 指数、腰围、C肽、体力活动和脂联素)。然后我们将使用弹性网 回归以选择对两个因素有贡献的最重要的代谢物 独立地回归和测试这些代谢特征与结直肠癌风险之间的关联 作为加工肉类消费的调解人。这个项目的目标是阐明生物 将炎症和代谢健康与结直肠癌联系起来的机制，并从长远来看，制定战略 优化饮食和生活方式干预，预防结直肠癌。Bever女士(PI)将在以下条件下进行这项研究 哈佛大学医学院流行病学和营养学教授Meir Stampfer博士的指导 公共卫生(HSPH)；宋明阳博士，临床流行病学和营养学助理教授 杰弗里·迈耶哈特博士，执业胃肠肿瘤学家和达纳-法伯研究所的研究员 哈佛大学医学院(HMS)癌症研究所、医学教授；梁黎明博士，副教授 HSPH统计遗传学教授；哈佛大学流行病学和营养学教授Edward Giovannucci博士 HSPH；安德鲁·陈博士，执业胃肠肿瘤学家和癌症流行病学主任 马萨诸塞州综合医院；医学教授兼副主任郑伟博士 范德比尔特大学医学中心的人口科学研究。贝弗是一名正在升入大学四年级的学生 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二年级 HSPH的理科博士课程。她的培训计划包括高级生物统计学和 流行病学方法、地方研讨会和国家会议，以及与导师的每周会议。这个 培训计划旨在支持贝弗女士成为一名医生-流行病学家的长期目标 具有癌症风险因素方面的专业知识。该计划包括在贝弗女士的 在她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.