Environmental Exposure and DNA Damage

环境暴露和 DNA 损伤

• 批准号: 7007396
• 负责人: JACK A TAYLOR
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7007396
• 关键词: DNA damage; biopsy; bladder neoplasm; bronchoscopy; cancer risk; chemical carcinogen; clinical research; early diagnosis; environment related neoplasm /cancer; environmental exposure; gel electrophoresis; gene environment interaction; gene mutation; human subject; laser capture microdissection; loss of heterozygosity; lung neoplasms; molecular oncology; neoplasm /cancer diagnosis; neoplasm /cancer genetics; neoplastic process; polymerase chain reaction; preneoplastic state; prognosis; tissue /cell culture; tumor suppressor genes

This area of my research tests the hypothesis that environmental exposures produce patterns of DNA damage. Such patterns can be used both to identify target genes and to suggest mutational mechanisms by which an environmental agent causes cancer. If specific carcinogens produce characteristic patterns of gene mutation in tumors, the detection of those patterns would be a powerful tool in studies of environmental risk and for use in prevention, early diagnosis, and prognosis. We are exploring this concept in our ongoing molecular epidemiologic and clinical studies designed to look at DNA damage in small biopsies of preneoplastic and normal tissue from target tissues and in normal lymphocytes. A long term goal is to develop a quantitative measure of the level of DNA mutation in normal tissue or "somatic mutational load". Such a metric could provide a tissue specific measure of lifetime environmental exposure, integrated across diet, genetic susceptibility, and repair, and might offer a more precise estimate of risk for cancer, neurologic, reproductive, and other diseases where DNA damage plays a role. Fluorescence Bronchoscopy and Molecular Characterization of Abnormal Bronchial Lesions (LIFE Study): This ongoing molecular clinical study at UNC Hospitals GCRC is designed to test the hypothesis that exposure correlates with the pattern of mutation in premalignant and normal lung tissues and that such mutations may have prognostic significance for lung cancer development. We are using the Lung Imaging Fluorescent Endoscope (LIFE), a sensitive bronchoscopy technique to collect normal, premalignant, and neoplastic tissue samples from patients at high risk of lung cancer from smoking, occupational exposures, or because of family history. These people are followed over a 2 year period with repeat bronchoscopies and biopsy allowing us to follow the molecular changes in individual lesions over time. In addition we have a small pilot project the VALID study, jointly funded with UNC, to obtain optimally-collected tumor and normal tissue from patients undergoing thoracotomy for lung cancer. Colon Cell DNA Damage Study: We have initiated a new pilot study at UNC Hospitals GCRC entitled: Inhibition of Fried Meat-Induced DNA Damage: A Dietary Intervention Study. The primary aim of this study is to assess genetic damage to colonic epithelium and blood lymphocytes induced by compounds in certain foods, in particular the pyrolysis products formed in cooked meat, as well as the putative protective effects of certain dietary compounds against that damage. This study will be among the few to examine the interaction of genotoxic dietary components with ?protective? components on a molecular level. It is the first use of the alkaline single cell-gel (Comet) assay in a controlled feeding study to detect DNA damage in colonic epithelial cells, rather than in target tissue surrogates like lymphocytes. In addition, this research will have implications for choosing the most appropriate intermediate outcomes that would be predictive of cancer in prospective cohort studies; it will also have implications for dietary recommendations and the methodological approach to future feeding studies of genotoxicity in humans.

我的研究领域检验了以下假设：环境暴露会产生DNA损伤模式。这种模式既可以用来识别靶基因，又提出了环境剂引起癌症的突变机制。如果特定的致癌物在肿瘤中产生基因突变的特征模式，那么对这些模式的检测将是研究环境风险以及用于预防，早期诊断和预后的强大工具。我们正在正在进行的分子流行病学和临床研究中探索这一概念，旨在研究靶组织和正常淋巴细胞中的肿瘤和正常组织的小活检中的DNA损伤。一个长期目标是制定正常组织中DNA突变水平或“体细胞突变负荷”的定量度量。这样的度量可以提供组织特定的终生环境暴露，跨饮食，遗传敏感性和修复的整合，并可能对DNA损害起作用的癌症，神经系统，生殖和其他疾病的风险进行更精确的估计。 荧光支气管镜检查和异常支气管病变的分子表征（生命研究）： UNC医院GCRC的这项正在进行的分子临床研究旨在检验以下假设：暴露与前态和正常肺组织中突变的模式相关，并且这种突变可能对肺癌发育具有预后意义。我们正在使用肺成像荧光内窥镜（LIFE），一种敏感的支气管镜技术来收集来自吸烟，职业暴露或家族病史的高风险患者的正常，预先和肿瘤组织样本。在两年的时间内，这些人遵循重复的支气管镜检查和活检，使我们能够随着时间的推移遵循各个病变的分子变化。此外，我们还有一个小型试点项目，由INC共同资助的有效研究从发生肺癌胸腔切开术的患者中获得最佳收集的肿瘤和正常组织。 结肠细胞DNA损伤研究： 我们已经在UNC医院开始了一项新的试点研究，题为：抑制炸肉诱导的DNA损害：一项饮食干预研究。这项研究的主要目的是评估某些食物中化合物诱导的结肠上皮和血液淋巴细胞的遗传损害，尤其是煮熟的肉中形成的热解产物，以及某些饮食化合物对这种损害的推定保护作用。这项研究将是少数研究遗传毒性饮食成分与保护性的相互作用的人之一？分子水平的成分。这是在受控的喂养研究中首次使用碱性单细胞 - 凝胶（彗星）测定法，以检测结肠上皮细胞中的DNA损伤，而不是在靶组织替代物（如淋巴细胞）中检测到DNA损伤。此外，这项研究将对选择前瞻性队列研究中可以预测癌症的最合适的中级结果有影响。这也将对饮食建议和人类遗传毒性的未来喂养研究产生影响。