Role of Vitamin D, Inflammation, and Energy Balance in Colorectal Cancer Survival

描述（由申请人提供）：对于影响结直肠癌诊断后生存的饮食和生活方式因素知之甚少。事实上，美国癌症协会的一个共识小组建议，“对营养和体育活动对癌症幸存者预后的影响进行适当的研究是迫切需要的，并且应该成为所有学术和研究资助机构的优先事项。”许多被认为影响结直肠癌进展的营养和生活方式因素（低维生素D、高胰岛素、肥胖和缺乏身体活动）可能通过细胞中的维生素D、炎症和能量平衡途径起作用。阐明这些因素与结直肠癌之间联系的生物学解释将提高营养和运动对癌症治疗至关重要的可接受性。为了解决这一问题，目前的建议侧重于研究结直肠癌复发和生存的生化、遗传和饮食预测因素，最终目标是降低死亡率。将研究三个相互关联的途径。在Aim 1中，我们将检查血浆维生素D水平、维生素D预测评分和途径内的遗传变异，以及这些暴露如何与特定分子改变相互作用。在Aim 2中，我们将研究炎症的血浆标志物和炎症相关基因的遗传变异，以更好地了解慢性炎症和结直肠癌之间的联系。此外，我们将探索这些炎症标志物与维生素D途径之间的相互作用。在Aim 3中，我们将研究一种新的饮食指数，该指数可评估长期全身胰岛素暴露，以及胰岛素样生长因子途径成员与维生素d之间的关系。该建议的主要优势在于能够前瞻性地检查这些血浆、遗传和饮食因素，使用三个大型结直肠癌患者队列，反复进行饮食和生活方式评估；存档的血液、肿瘤和DNA标本；以及有关预后因素和癌症结果的综合数据。通过研究这些目标，该项目将提高对结直肠癌发病机制的理解，并为这种困难的疾病确定实际的治疗措施。此外，目前的提案将允许候选人获得生物统计学和流行病学的高级技能，从事结直肠癌研究的重点项目，并获得经验丰富且成功的研究人员的密切，长期的指导，促进她向独立的学术研究人员过渡。丹娜-法伯/哈佛癌症中心、钱宁实验室和哈佛公共卫生学院的紧密合作和丰富资源为候选人提供了一个理想的环境，让他接受必要的培训和指导，成为癌症研究领域的领导者。

DESCRIPTION (provided by applicant): Relatively little is known about the dietary and lifestyle factors that influence survival after a diagnosis of colorectal cancer. In fact, a consensus panel of the American Cancer Society recommended, "Properly conducted studies of the effect of nutrition and physical activity on the prognosis of cancer survivors are urgently needed, and should be a high priority for all academic and research funding agencies." Many of the nutritional and lifestyle factors that are thought to influence colorectal cancer progression (low vitamin D, high insulin, obesity, and physical inactivity) may operate through the vitamin D, inflammatory, and energy balance pathways in the cell. Elucidating the biological explanation for the link between these factors and colorectal cancer would enhance the acceptability of nutrition and exercise as critical for cancer treatment. To address this problem, the current proposal focuses on the investigation of biochemical, genetic, and dietary predictors of colorectal cancer recurrence and survival, with the ultimate goal of reducing mortality. Three inter-related pathways will be studied. For Aim 1, we will examine plasma levels of vitamin D, a vitamin D prediction score, and genetic variation within the pathway, and how these exposures interact with specific molecular alterations. For Aim 2, we will investigate plasma markers of inflammation and genetic variation in inflammation-related genes, in an effort to better understand the link between chronic inflammation and colorectal cancer. In addition, we will explore the interaction between these inflammatory markers and the vitamin D pathway. For Aim 3, we will examine a novel dietary index that estimates long-term systemic insulin exposure, as well as the relationship between members of the insulin-like growth factor pathway and vitamin D. A major strength of this proposal is the ability to examine these plasma, genetic, and dietary factors prospectively, using three large cohorts of colorectal cancer patients with repeated dietary and lifestyle assessments; archived blood, tumor, and DNA specimens; and comprehensive data on prognostic factors and cancer outcomes. By examining these aims, this project will improve the understanding of the mechanisms that underlie colorectal cancer pathogenesis and define practical treatment measures for this difficult disease. Moreover, the current proposal will allow the candidate to gain advanced skills in biostatistics and epidemiology, pursue a focused program in colorectal cancer research, and receive close, long-term mentorship from experienced and successful investigators, promoting her transition to an independent academic researcher. The intense collaboration and vast resources of the Dana-Farber/Harvard Cancer Center, Channing Laboratory, and Harvard School of Public Health provide an ideal environment for the candidate to receive the training and mentorship needed to become a leader in the field of cancer research.