VDR Variants, Nutrient Intakes, and Adenoma Recurrence

描述（由申请人提供）：我的长期职业目标是应用来自几个不同学科的方法，包括流行病学，营养学，分子生物学和统计学，设计和测试为转化癌症预防研究做出重要贡献的假设。为了实现这一目标，需要进一步的培训，目前的建议旨在回答重要的研究问题，并在这些领域提供培训。流行病学和实验室研究表明，饮食中维生素D和钙的摄入可能与结直肠肿瘤的风险降低有关，维生素D受体（VDR）的多态性也可能与风险有关。此外，最近有报道称，潜在致癌的胆汁酸石胆酸（LCA）是VDR的配体。LCA-VDR结合对结直肠肿瘤的影响尚不清楚。因此，我们建议进行一项研究，以调查是否VDR多态性与结直肠腺瘤复发的风险，以及这种关联是否被修改的饮食摄入的维生素D，钙和脂肪。来自独立营养干预试验的两个研究人群的组合将为我们提供约2500名参与者，并使我们能够进行迄今为止此类最大规模的流行病学研究。此外，我们将有能力进行分子生物学实验，以测试VDR在结直肠肿瘤中的功能作用，包括VDR多态性和LCA结合在结肠癌细胞系中的翻译作用。完成这些目标将需要在流行病学设计和分析、基因-营养相互作用的统计分析以及实验室实验的分子方法方面进行全面和详细的培训。本提案的申办者大卫艾伯茨博士和共同申办者马克·豪斯勒博士、埃琳娜·马丁内斯博士和西尔万·绿色博士将各自提供专业知识、指导和支持，以顺利完成拟议的研究。亚利桑那大学的亚利桑那癌症中心（ACC）拥有来自不同背景的教师，一流的实验室设施，并为癌症预防事业的发展提供了良好的环境。ACC的资源，课程和实践经验将结合在一个旨在帮助我在转化癌症预防研究中追求成功的职业生涯的计划中。

DESCRIPTION (provided by applicant): My long-term professional goal is to apply methodology from several different disciplines, including epidemiology, nutrition, molecular biology, and statistics, to design and test hypotheses that make important contributions to translational cancer prevention research. Further training is required in order to achieve this goal, and the current proposal had been designed to both answer important research questions and to provide training in these areas. Epidemiological and laboratory research has shown that dietary intake of vitamin D and calcium may be associated with a decreased risk of colorectal neoplasia, and that polymorphisms of the vitamin D receptor (VDR) may also be associated with risk. In addition, it was recently reported that the potentially carcinogenic bile acid lithocholic acid (LCA) is a ligand for the VDR. The effects of LCA-VDR binding on colorectal neoplasia are unknown. Therefore, we propose to conduct a study to investigate whether VDR polymorphisms are associated with the risk of colorectal adenoma recurrence, and whether this association is modified by dietary intake of vitamin D, calcium, and fat. The combination of two study populations from separate nutrition intervention trials will provide us with approximately 2500 participants and allow us to perform the largest epidemiological study of this kind to date. In addition, we will have the ability to conduct experiments in molecular biology to test the functional role of the VDR in colorectal neoplasia, including the translational effects of VDR polymorphisms and LCA binding in colon cancer cell lines. Completion of these objectives will require thorough and detailed training in epidemiological design and analysis, statistical analyses of gene-nutrient interactions, and molecular approaches to laboratory experimentation. The sponsor for this proposal, Dr. David Alberts, and cosponsors, Dr. Mark Haussler, Dr. Elena Martinez, and Dr. Sylvan Green will each provide expertise, guidance, and support for the successful completion of the proposed research. The Arizona Cancer Center (ACC) at the University of Arizona has faculty from diverse backgrounds, excellent laboratory facilities, and provides an outstanding environment for development of a career in cancer prevention. The resources at the ACC, coursework, and practical experience will be combined in a program designed to assist me in pursuing a successful career in translational cancer prevention research.