LOCALIZED VITAMIN DEFICIENCIES AND RISK FOR LUNG CANCER

描述：(申请人的描述)虽然有大量的 高密度脂蛋白保护作用的流行病学和实验证据 摄入水果和蔬菜对抗肺癌(LC)，有研究表明 分离特定营养效应的尝试给出了不同的结果。 两项研究之间缺乏一致性的一个可能原因 个别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等成分 蔬菜可能不是唯一的保护成分。我们推进了 水果和蔬菜中的叶酸可能是这些相对 未研究的成分。存在缺陷的潜在机制 叶酸和相关的维生素B-12可能通过DNA导致基因损伤 低甲基化是众所周知的。此外，化学成分还包括 香烟烟雾已被证明与叶酸和维生素B-12相互作用， 将它们转化为生物活性不强的化合物。这些化学物质 可能具有生理意义的反应得到了以下报告的支持 吸烟者的循环和口腔粘膜叶酸水平较低， 补充叶酸/B-12对支气管化生的反应。我们预计 吸烟对肺部的影响最大，在那里有潜在的 香烟烟雾对微量营养素的氧化和破坏应该是最大的 已经宣布了。然而，叶酸和维生素B-12在预防LC中的重要性 没有得到广泛的赏识。目前还没有关于测量的报告 肺组织中的叶酸或维生素B-12水平。尽管有一些 关于上皮衬里液体(ELF)中维生素C和维生素E水平的报告，以及 吸烟者的肺泡巨噬细胞(AM)蓄积 研究人员在同一样本中测量了一组维生素，研究了 AM积累维生素的意义，或者最重要的是，相关 那些表达中间终点生物标志物的维生素 (IEB)。LC中IEB的鉴定进展顺利，但研究 早期事件的年表还处于初级阶段。因此， 将特别强调IEB的识别和验证 在肺癌发生中的作用，因为这是一个没有充分记录但正在出现的 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方面的强化培训 在专家指导下进行研究，成为这方面的独立研究员 区域。随后，膳食摄入量和叶酸浓度， ELF、AM、支气管活检中的维生素B-12、A、E、C和β-胡萝卜素， 血液将与全球DNA低甲基化和IEB一起测量 吸烟者和非吸烟者的支气管活检在年龄、性别和 种族。除了确定和确认IEB外，拟议的研究还将 提供对记录良好的保护机制的洞察 水果、蔬菜和抗氧化剂营养素对罹患癌症风险的影响 并将提供亟需的基线数据，以便 维生素的化学预防应用评价。这些活动， 随着流行病学和统计分析的高级研究和 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.