The DNA adductome of lung carcinogenesis

肺癌发生的DNA加合物

• 批准号: 9897494
• 负责人: Silvia Balbo
• 金额: $ 35.17万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-04 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9897494
• 关键词: 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; Diagnostic; 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; Structure; Techniques; Testing; Therapeutic; Time; Tobacco; Tobacco smoke; Tobacco use; Work; adduct; base; carcinogenicity; cell growth; cigarette smoke; design; epidemiology study; experimental study; innovation; lung carcinogenesis; non-smoker; screening; smoking cessation; tobacco exposure; tool

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 肺癌是全球最常见的癌症，2012年占160万人死亡，158,000人死亡 2015年美国的死亡。尽管香烟烟在这种流行病中扮演着明显的作用，但具有确切机制 通过这种癌症发展的尚不清楚。尽管有反吸烟运动，但2014年仍然有40 美国的百万吸烟者在全球范围内超过10亿。预防和治疗的更有效策略 在这种疾病中，需要更好的工具来了解肺癌病因学和发育的机制。 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损失 机制和肺癌。其中许多研究使用相对非特异的技术，例如 免疫测定和32p预标签清楚地表明，DNA加合物水平较高 吸烟者比非吸烟者，这与吸烟者肺中发现的多重突变一致。 但是，使用这些非特异性技术并未导致任何任何 DNA加合物，因此在清楚地识别其形成机制的情况下。其他研究 针对特定DNA加合物的针对特定的DNA，导致了一些化学表征的DNA的鉴定 加合物，但这些结果并不能解释使用更通用的非特异性方法发现的结果。精确 肺癌发生过程中DNA损伤的表征既精确又全面保留 难以捉摸。我们已经开发了一种新的基于质谱的DNA加合体方法 DNA加合物的全面高分辨率分析并提供有关其分裂的信息 允许结构阐明。我们的长期目标是确定表征的DNA损伤曲线 肺癌发生以鉴定DNA加合物最终用于早期检测预防和 治疗。我们的假设是，使用我们的方法将结合非特异性方法的筛选能力 过去用于检测到各种修饰的特定化学表征，从而导致 特定的内核轮廓。此应用程序的目标是：1。表征肺DNA中加合物 动物模型使用烟草特异性亚硝胺NNK诱导肺癌并识别驱动器加合物 通过共同暴露于促炎剂脂多糖（LPS）来增强其影响； 2 随着时间的推移，在这些模型中表征DNA加合体的演变，以阐明 炎症和内源性过程； 3。为吸烟者的肺DNA中的DNA加合物表征 将其与非吸烟者和动物模型中鉴定的曲线进行比较。我们的结果将 表征与NNK和NNK+LPS相关的加合体诱导的肺癌发生，并 吸烟者的肺DNA中的加合物，为鉴定分子特征奠定了基础 人分子流行病学研究中癌症病因的研究。 1