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.

我的这一研究领域检验了环境暴露会产生 DNA 损伤模式的假设。这种模式既可以用来识别靶基因，也可以用来提示环境因素导致癌症的突变机制。如果特定的致癌物在肿瘤中产生特征性的基因突变模式，那么对这些模式的检测将成为环境风险研究以及预防、早期诊断和预后的有力工具。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，这些研究旨在观察来自靶组织的癌前组织和正常组织以及正常淋巴细胞的小活检中的 DNA 损伤。长期目标是开发一种定量测量正常组织中 DNA 突变水平或“体细胞突变负荷”的方法。这样的指标可以提供一生中环境暴露的组织特异性测量，整合饮食、遗传易感性和修复，并且可以更精确地估计癌症、神经系统疾病、生殖疾病和其他 DNA 损伤发挥作用的疾病的风险。 荧光支气管镜检查和异常支气管病变的分子特征（LIFE 研究）： 北卡罗来纳大学医院 GCRC 正在进行的这项分子临床研究旨在检验以下假设：暴露与癌前和正常肺组织的突变模式相关，并且此类突变可能对肺癌的发展具有预后意义。我们使用肺成像荧光内窥镜 (LIFE)，这是一种灵敏的支气管镜检查技术，从因吸烟、职业暴露或家族史而患肺癌高风险的患者中收集正常、癌前和肿瘤组织样本。这些人经过两年的重复支气管镜检查和活检进行随访，使我们能够跟踪各个病变随时间的分子变化。此外，我们还有一个小型试点项目 VALID 研究，与北卡罗来纳大学联合资助，旨在从因肺癌开胸手术的患者身上获取最佳收集的肿瘤和正常组织。 结肠细胞 DNA 损伤研究： 我们在北卡罗来纳大学 GCRC 医院启动了一项新的试点研究，题为：抑制油炸肉引起的 DNA 损伤：饮食干预研究。本研究的主要目的是评估某些食物中的化合物（特别是熟肉中形成的热解产物）对结肠上皮和血液淋巴细胞造成的遗传损伤，以及某些膳食化合物对这种损伤的假定保护作用。这项研究将是为数不多的研究遗传毒性膳食成分与“保护性”相互作用的研究之一。分子水平上的成分。这是首次在控制喂养研究中使用碱性单细胞凝胶（彗星）测定来检测结肠上皮细胞中的 DNA 损伤，而不是淋巴细胞等靶组织替代物中的 DNA 损伤。此外，这项研究将对在前瞻性队列研究中选择最合适的预测癌症的中间结果产生影响；它还将对饮食建议和未来人类遗传毒性喂养研究的方法产生影响。