LOCALIZED VITAMIN DEFICIENCIES AND RISK FOR LUNG CANCER

描述：（申请人的描述）虽然存在大量的 流行病学和实验证据表明， 摄入水果和蔬菜对肺癌（LC），研究， 试图分离出特定的养分效应，得到了不同的结果。 研究之间缺乏一致性的一个可能原因是 个人营养素和水果和蔬菜是，经常 研究了水果中的β-胡萝卜素和其他抗氧化剂， 蔬菜可能不是唯一的保护成分。 我们推进 水果和蔬菜中的叶酸可能是这些相对 未研究的组件 这些缺陷的潜在机制 叶酸和相关的维生素B-12，可通过DNA导致基因损伤 低甲基化是很好理解。 此外， 香烟烟雾已经显示与叶酸和维生素B-12相互作用， 将其转化为生物活性化合物。 这些化学 这些反应可能具有生理意义，这得到以下报告的支持： 吸烟者的循环和口腔粘膜叶酸水平较低， 支气管化生对叶酸/B-12补充的反应。 我们预计 吸烟对肺部的影响最大， 香烟烟雾氧化和破坏微量营养素应该是最 宣布 然而，叶酸和维生素B-12在预防LC中的重要性 并没有得到广泛的认可。 没有关于测量 肺组织中叶酸或维生素B-12水平。 虽然有一些 报告维生素C和E的上皮细胞衬液（ELF）水平，以及 吸烟者肺泡巨噬细胞（AM）的积累，这些都没有 研究测量了同一样本中的一组维生素，研究了 AM积累维生素的意义，或者最重要的是， 那些具有中间终点生物标志物表达的维生素 （IEB）。 LC中IEB的鉴定进展迅速，但研究 对早期事件年表的研究才刚刚起步 因此，我们认为， 将特别强调IEB的识别和验证 在肺癌发生中，因为这是一个没有充分记录的，但正在出现的 癌症预防研究领域。 这五年的预防肿瘤学 学术奖将为申请人提供IEB的强化培训 在专家指导下进行研究，成为这方面的独立研究人员 区 在此之后，膳食摄入量和叶酸浓度， 维生素B-12、A、E、C和ELF、AM、支气管活检中的β-胡萝卜素， 血液将沿着整体DNA低甲基化和IEB， 吸烟者和非吸烟者的支气管活检，年龄、性别和 比赛 沿着识别和验证IEB，拟议的研究将 深入了解有据可查的保护机制 水果，蔬菜和抗氧化营养素对风险的影响 吸烟者的肺癌，并将提供急需的基线数据， 评价维生素的化学预防应用。 这些活动， 沿着流行病学和统计分析的高级研究， 教学经验，将提供职业生涯所需的专业知识， 成功的独立调查员

DESCRIPTION: (Applicant's Description) Although there is substantial epidemiological and experimental evidence of a protective effect of a high intake of fruits and vegetables against lung cancer (LC), studies that have attempted to isolate specific nutrient effects have given variable results. One possible reason for the lack of consistency between studies of individual nutrients and fruits and vegetables is that the frequently studied components like beta-carotene and other antioxidants in fruits and vegetables may not be the only protective components. We advance the possibility that folate in fruits and vegetables is one of these relatively unstudied components. The potential mechanisms whereby deficiencies of folate and inter-related vitamin B-12, could lead to gene damage via DNA hypomethylation are well understood. Furthermore, chemical components of cigarette smoke have been shown to interact with folate and vitamin B-12, transforming them into biologically inactive compounds. That these chemical reactions may have physiologic significance is supported by the reports of lower circulating and buccal mucosal folate levels in smokers, and a response of bronchial metaplasia to folate/B-12 supplementation. We expect the effect of smoking to be greatest in the lung, where the potential for cigarette smoke to oxidize and destroy micronutrients should be most pronounced. Yet, the importance of folate and vitamin B-12 in LC prevention is not widely appreciated. There are no reports on the measurement of folate or vitamin B-12 levels in lung tissue. Although there are some reports on the epithelial lining fluid (ELF) levels of vitamins C and E, and their accumulation by alveolar macrophages (AM) of smokers, none of these studies has measured a battery of vitamins in the same sample, studied the significance of AM accumulation of vitamins, or most importantly, correlated those vitamins with the expression of intermediate endpoint biomarkers (IEB). The identification of IEB in LC has proceeded briskly, but studies of the chronology of early events are only in their infancy. Therefore, special emphasis will be given to the identification and validation of IEB in lung carcinogenesis since this is an inadequately documented but emerging area in cancer prevention research. This five-year Preventive Oncology Academic Award will provide the applicant with intensive training in IEB research under expert guidance to become an independent researcher in this area. Following this, the dietary intake and concentrations of folate, vitamins B-12, A, E, C, and beta-carotene in ELF, AM, bronchial biopsies, and blood will be measured along with global DNA hypomethylation and IEB in bronchial biopsies of smokers and non smokers matched for age, gender, and race. Along with identifying and validating IEB, the proposed studies will provide insight into the mechanisms for the well-documented protective effects of fruits, vegetables, and antioxidant nutrients on the risk for lung cancer in smokers, and will provide much needed base-line data for the evaluation of chemopreventive applications of vitamins. These activities, along with advanced studies of epidemiology and statistical analysis and experience in teaching, will provide the expertise needed for a career as a successful, independent investigator.