Metabolic mechanisms of naphthalene toxicity in lung

 描述（由申请方提供）：萘（NA）是一种急性呼吸道毒物，也是一种潜在的人类肺癌致癌物。人类暴露于NA是广泛的，但人类对NA毒性的易感性知之甚少。关于人类对NA毒性敏感性的裁决将对公共卫生产生重大影响，可以挽救许多生命，但涉及经济成本。该ViCTER计划的总体主题是研究NA诱导的肺毒性机制，包括耐受性，以改善NA和其他相关毒物对人类肺癌风险的评估。提出了三个目的：1）通过直接机制确定NA是否是遗传毒性致癌物; 2）测试炎性细胞雌激素产生在NA诱导的肺毒性和耐受性中的作用; 3）鉴定NA诱导的肺毒性和耐受性的细胞应激反应。这些目标通过研究初始生物活化步骤下游的分子和细胞事件，显着扩大了当前项目的范围，而母基金则专注于NA生物活化步骤。该联盟允许参与者之间进行广泛的合作，分享动物模型，独特的技能（例如，气道解剖）、仪器和分子、细胞和遗传毒性观点。来自目标的数据将为NA诱导的组织损伤和修复的复杂多步骤过程提供补充观点，这些过程导致肿瘤前变化和最终致癌。目的1将提供关于NA是否在体内肺中诱导稳定的DNA加合物的急需的数据，并将我们的研究转化为更像人类的模型系统。这些结果将推动风险评估，指导未来的机理研究，并为测试其他致癌物提供方法和途径。目的2将产生一种新的基因敲除小鼠模型，并建立巨噬细胞来源的雌激素在NA诱导的过度增殖反应和耐受中的作用，这先于增生/发育不良结节的发展。目的3将确定特定的活性氧损伤驱动急性肺毒性和信号通路，允许NA诱导的耐受性。这些结果将为未来的转化研究提供潜在的缓解剂和生物标志物，以识别和保护高危人群。

 DESCRIPTION (provided by applicant): Naphthalene (NA) is an acute respiratory toxicant and a potential human lung carcinogen. Human exposure to NA is widespread, but human susceptibility to NA toxicity is poorly understood. The verdict on human susceptibility to NA toxicity will have a significant impact on public health, could save many lives, but involves economic costs. The overall theme of this ViCTER program is to study mechanisms of lung toxicity, including tolerance, induced by NA, in order to improve assessment of human lung cancer risks from NA and other related toxicants. Three Aims are proposed, 1) to define whether NA is a genotoxic carcinogen through a direct mechanism; 2) to test the role of inflammatory cell estrogen production in NA-induced lung toxicity and tolerance; and 3) to identify cellular stress response for NA-induced lung toxicity and tolerance. These Aims significantly expand the scope of the current project by studying molecular and cellular events downstream of the initial bio-activation step, while the parent grant is focused on the NA bio-activation step. The consortium allows extensive collaborations among the participants, in sharing of animal models, unique skills (e.g., airway dissection), instruments, and molecular, cellular, and genotoxic perspectives. Data from the Aims will provide complementary views of the complex, multi-step process of NA-induced tissue damage and repair that lead to preneoplastic changes and eventual carcinogenesis. Aim 1 will provide much needed data on whether NA induces stable DNA adducts in the lung in vivo, and will translate our studies to a more human-like model system. The results would drive risk estimation, guide future mechanistic studies, and provide methodology and approaches for testing other carcinogens. Aim 2 will produce a novel knockout mouse model and establish role of macrophage-derived estrogen in NA-induced hyper proliferative response and tolerance, which precedes development of hyperplastic/dysplastic nodules. Aim 3 will identify the specific reactive oxygen species damage driving acute lung toxicity and signaling pathways that allow for NA-induced tolerance. The results would provide insight for potential mitigating agents and biomarkers for future translational studies to identify and protect at-risk individuals.