The DNA adductome of lung carcinogenesis

肺癌发生的DNA加合物

基本信息

批准号：
10372034
负责人：
Silvia Balbo
金额：
$ 34.47万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-04 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10372034
关键词：
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone A/J Mouse Accounting Aldehydes Animal Model Antismoking Aromatic Polycyclic Hydrocarbons Cancer Etiology Cessation of life Chemicals Chronic Complex DNA DNA Adducts DNA Damage DNA Modification Process DNA analysis Development Disease Dose Early Diagnosis Epidemic Evolution Exposure to Generations Goals Human Immunoassay Inflammation Inflammatory Investigation Lead Lipid Peroxidation Lipopolysaccharides Lung Malignant Neoplasms Malignant neoplasm of lung Mass Spectrum Analysis Methodology Methods Modeling Modification Molecular Molecular Epidemiology Molecular Profiling Monitor Mutation Nature Nicotine Nitrosamines Outcome Oxidative Stress Pathway interactions Prevention Prevention strategy Preventive Process Rattus Resolution Role Screening Result Series Smoker Techniques Testing Therapeutic Time Tobacco Tobacco smoke Tobacco use Work adduct base carcinogenicity cell growth cigarette smoke design diagnostic strategy epidemiology study experimental study innovation lung carcinogenesis non-smoker screening smoking cessation tobacco exposure tool

项目摘要

SUMMARY Lung cancer is the most common cancer worldwide, accounting for 1.6 million deaths in 2012 and for 158,000 deaths in the US in 2015. Despite the clear role of cigarette smoke in this epidemic, the precise mechanisms through which this cancer develops remain unclear. Despite anti-smoking campaigns, in 2014 there were still 40 million smokers in the U.S. and over 1 billion worldwide. More effective strategies for prevention and treatment of this disease, demand better tools to understand the mechanisms of lung cancer etiology and development. Numerous studies have shown that chemicals present in tobacco smoke induce DNA modifications (DNA adducts) which if not repaired, can lead to mutations ultimately resulting in loss of normal cellular growth control mechanisms and lung cancer. Many of these studies, using relatively non-specific techniques such as immunoassay and 32P-postlabelling, have clearly shown that DNA adduct levels are higher in the lungs of smokers than non-smokers, which is consistent with the multiple mutations found in the lungs of smokers. However, use of these non-specific techniques has not resulted in the positive structural characterization of any DNA adduct, and thus on a clear identification of the mechanisms involved in their formation. Other studies targeted at specific DNA adducts, have resulted in the identification of a few chemically characterized DNA adducts, but these results do not explain those found using the more general non-specific approaches. A precise characterization of the DNA damage during lung carcinogenesis that is both precise and comprehensive remains elusive. We have developed a new mass spectrometry based DNA adductomic approach performing comprehensive high resolution analysis of DNA adducts and providing information on their fragmentation allowing for structural elucidation. Our long-term goal is to determine the DNA damage profile characterizing lung carcinogenesis to identify a DNA adductome that may be ultimately used for early detection prevention and treatment. Our hypothesis is that with our method will combine the screening ability of the non-specific methods used in the past with the specific chemical characterization of the various modifications detected, resulting in a specific adductomic profile. The objectives of this application are: 1. to characterize the lung DNA adductome in animal models using the tobacco specific nitrosamine NNK to induce lung cancer and identify the driver adducts by enhancing its effects by co-exposure to the pro-inflammatory agent lipopolysaccharide (LPS); 2. to characterize the evolution of the DNA adductome in these models over time, clarifying the contribution of inflammation and endogenous processes; 3. to characterize the DNA adductome in smokers' lung DNA comparing it to non-smokers and to the profile identified in the animal models. Collectively our results will characterize the adductome associated with NNK and NNK+LPS induced lung carcinogenesis and the adductome in the lung DNA of smokers, setting the stage for the identification of molecular signatures for the investigation of cancer etiology in human molecular epidemiology studies. 1

概括肺癌是全世界最常见的癌症，2012 年导致 160 万人死亡，其中 158,000 人死于肺癌 2015 年美国死亡人数。尽管香烟烟雾在这场流行病中发挥了明显的作用，但其确切机制这种癌症的发生过程尚不清楚。尽管开展了反吸烟运动，2014 年仍有 40 美国有 10 亿烟民，全球有超过 10 亿烟民。更有效的预防和治疗策略对于这种疾病的研究，需要更好的工具来了解肺癌的病因和发展机制。大量研究表明，烟草烟雾中存在的化学物质会诱导 DNA 修饰（DNA 加合物），如果不修复，可能会导致突变，最终导致正常细胞生长控制的丧失机制与肺癌。其中许多研究使用相对非特定的技术，例如免疫测定和 32P 后标记清楚地表明，DNA 加合物水平在肺中较高吸烟者的患病率高于不吸烟者，这与吸烟者肺部发现的多种突变一致。然而，这些非特异性技术的使用并没有导致任何积极的结构表征。 DNA 加合物，从而清楚地鉴定其形成所涉及的机制。其他研究针对特定 DNA 加合物，已鉴定出一些具有化学特征的 DNA 加合物，但这些结果并不能解释使用更一般的非特异性方法发现的结果。一个精确的肺癌发生过程中 DNA 损伤的表征仍然是精确且全面的难以捉摸。我们开发了一种新的基于质谱分析的 DNA 加合方法 DNA 加合物的全面高分辨率分析并提供有关其碎片的信息以便进行结构阐明。我们的长期目标是确定 DNA 损伤特征肺癌发生过程，以确定 DNA 加合物，最终可用于早期检测和预防治疗。我们的假设是，我们的方法将结合非特异性方法的筛选能力过去使用过检测到的各种修饰的特定化学特征，从而产生特定的内收轮廓。本申请的目的是： 1. 表征肺 DNA 加合物组使用烟草特异性亚硝胺 NNK 诱导肺癌并鉴定驱动加合物的动物模型通过同时接触促炎剂脂多糖（LPS）来增强其效果； 2. 到描述这些模型中 DNA 加合物随时间的演变，阐明了炎症和内源性过程； 3. 表征吸烟者肺 DNA 中的 DNA 加合物将其与非吸烟者以及动物模型中确定的概况进行比较。总的来说，我们的结果将表征与 NNK 和 NNK+LPS 诱导的肺癌发生相关的加合物组以及吸烟者肺部 DNA 中的加合体，为识别吸烟者的分子特征奠定了基础人类分子流行病学研究中癌症病因学的调查。 1