Calcium and Colorectal Cancer: Gene-Environment Interactions and Molecular Pathways

 描述（由申请人提供）：尽管结肠镜检查的使用越来越多，治疗也得到了改善，但结直肠癌（CRC）仍然是美国男性和女性中第三大常见癌症和癌症相关死亡。我的长期职业目标是成为一名独立的学术研究者，能够应用分子病理流行病学和遗传流行病学方法来开发新的CRC预防和控制策略。我渴望将流行病学工作中观察到的相关性与CRC病因学和预后联系起来，从而阐明新的生物学机制，并最终降低CRC的发病率和死亡率。为了实现这一目标，这个K 07奖将使我能够接受分子病理流行病学，肿瘤组织收集和使用，癌症生存以及遗传流行病学方法的新培训。培训将包括指导研究，原发性肿瘤组织数据收集，病理学实验室实习，参与建立多中心癌症幸存者队列，教学课程，在同行评审期刊上发表我的研究，参加科学会议，并提交R 01资助。这项研究解决了关于钙在CRC病因学和预后中作用的三个关键知识空白：CRC亚型的病因异质性（目的1），CRC风险的基因-环境相互作用（目的2）和CRC生存的预后意义（目的3）。为了解决这些差距，我提出了一种新的综合方法，将利用四个独特的和丰富的人口为基础的研究：护士健康研究，护士健康研究II，卫生专业人员随访研究，和遗传学和流行病学的结直肠癌联盟（GECCO）。这项研究将是最大的检查钙结合肿瘤病理标志物和遗传变异对CRC病因和预后的作用。其发现可能具有重要的病因学和临床意义，包括1）揭示新的预后标志物和生物学机制; 2）为未来的饮食指南提供信息，以降低CRC的风险; 3）为改善美国120万受这种致命疾病折磨的人的生存提供新的见解。这项培训和研究得到了哈佛一群经验丰富的导师的支持。Edward Giovannucci博士将监督培训和研究的各个方面。我将获得新的培训，在分子病理流行病学与Dr. Dr. Ogino，癌症生存与Dr. Charles Fuchs，和遗传流行病学方法与Dr. Peter Kraft。我也得到了哈佛的Donna Spiegelman博士和Fred哈钦森癌症研究中心的Ulrike Peters博士的合作承诺。在获奖完成后，我有信心实现研究独立性，并显着提高我的能力，以创新和重要的方式为CRC流行病学领域做出贡献。

 DESCRIPTION (provided by applicant): Despite the increasing use of colonoscopy and improved treatment, colorectal cancer (CRC) remains the third most common cancer and cancer-related death in both US men and women. My long-term career goal is to become an independent academic investigator with the ability to apply molecular pathological epidemiology and genetic epidemiology methods to develop new prevention and control strategies for CRC. I aspire to bridge the associations observed in epidemiological work with CRC etiology and prognosis, thereby illuminating new biological mechanisms and, ultimately, decreasing CRC incidence and mortality. To achieve this goal, this K07 award will enable me to receive new training in molecular pathological epidemiology, tumor tissue collection and usage, cancer survivorship, as well as genetic epidemiology methods. The training will include mentored research, primary tumor tissue data collection, pathology laboratory internship, involvement in establishing a multi-center cancer survivor cohort, didactic coursework, publication of my research in peer- reviewed journals, attendance at scientific meetings, and submission of an R01 grant. The proposed research addresses three critical gaps in knowledge regarding the role of calcium in CRC etiology and prognosis: the etiologic heterogeneity of CRC sub-types (Aim 1), gene-environment interaction on CRC risk (Aim 2), and prognostic implications for CRC survival (Aim 3). To address these gaps, I propose a novel and integrated approach that will leverage four unique and rich population-based studies: the Nurses' Health Study, Nurses' Health Study II, Health Professionals Follow-Up Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). This study will be the largest to examine the role of calcium in combination with tumor pathological markers and genetic variants on the etiology and prognosis of CRC. Its findings could have significant etiologic and clinical implications, including 1) revealing new prognostic markers and biological mechanisms; 2) informing future dietary guidelines to lower the risk of CRC; and 3) offering new insights for improving survival among the 1.2 million people in the US who are afflicted by this deadly disease. This training and research is supported by a group of experienced mentors at Harvard. Dr. Edward Giovannucci will supervise all aspects of the training and research. I will obtain new training in molecular pathological epidemiology with Dr. Shuji Ogino, cancer survivorship with Dr. Charles Fuchs, and genetic epidemiology methods with Dr. Peter Kraft. I also have a pledge of collaboration from Drs. Donna Spiegelman at Harvard and Ulrike Peters at the Fred Hutchinson Cancer Research Center. At the completion of the award, I am confident to achieve research independence and significantly enhance my ability to contribute to the field of CRC epidemiology in innovative and important ways.