Metabolic mechanisms of naphthalene toxicity in lung

萘肺毒性的代谢机制

基本信息

批准号：
8814765
负责人：
Xinxin Ding
金额：
$ 42.77万
依托单位：
STATE UNIVERSITY OF NEW YORK AT ALBANY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-20 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8814765
关键词：
Abbreviations Acute Acute Lung Injury Animal Model Animals Aromatase Automobile Driving Belief Biological Markers Biological Models Carcinogens Cell Proliferation Cells Cellular Stress Response Collaborations Complex Cytochrome P450 DNA DNA Adducts Data Development Dissection Drug Metabolic Detoxication Environmental Pollutants Enzymes Epithelial Epoxy Compounds Estrogens Event Exposure to Fostering Future Goals Human Hyperplasia Immune In Vitro Individual Infiltration Inflammatory Inhalation Toxicology Injury Intervention Knockout Mice Knowledge Lead Liver Lung Lung Inflammation Macaca mulatta Malignant neoplasm of lung Mediating Metabolic Metabolic Activation Metabolic Biotransformation Methodology Methods Molecular Mus Myeloid Cells Naphthalene Naphthoquinones Nodule Organ Outcome Parents Participant Play Predisposition Preneoplastic Change Process Production Proteins Public Health Reactive Oxygen Species Research Respiratory System Respiratory tract structure Risk Role Sampling Signal Pathway Signal Transduction Structure of parenchyma of lung System Technology Testing Tissues Toxic effect Translating accelerator mass spectrometry biological adaptation to stress cancer risk carcinogenesis carcinogenicity cytotoxicity design disorder prevention economic cost exposed human population genotoxicity human SLC25A5 protein improved in vivo injury and repair insight instrument interdisciplinary collaboration lung tumorigenesis macrophage mouse model novel parent grant parent project programs public health relevance repaired respiratory response skills stressor tissue repair toxicant translational study

项目摘要

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.

描述（由适用提供）：萘（NA）是急性呼吸有毒物质和潜在的人肺癌。人类对NA的暴露是广泛的，但是人类对NA毒性的敏感性知之甚少。对人类对NA毒性的敏感性的判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。这个Victer计划的总体主题是研究NA引起的肺毒性机制，包括耐受性，以改善对NA和其他相关毒物的人类肺癌风险的评估。提出了三个目标，1）通过直接机制来定义Na是否是遗传毒性致癌； 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）确定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激活步骤下游的分子和细胞事件可以显着扩大当前项目的范围，而父母的赠款则集中在NA生物激活步骤上。该财团允许参与者之间进行广泛的合作，共享动物模型，独特的技能（例如气道解剖），仪器以及分子，细胞和遗传毒性的观点。来自目标的数据将提供复杂的多步目标1的完整视图，将提供急需的数据，以了解NA诱导的组织损伤和修复是否导致肿瘤性变化和最终的致癌作用。 AIM 1将提供急需的数据，以了解Na在体内是否诱导肺中稳定的DNA加合物，并将我们的研究转化为更类似人类的模型系统。结果将推动风险估计，指导未来的机械研究，并提供测试其他致癌物的方法和方法。 AIM 2将产生一种新颖的敲除小鼠模型，并建立AIM 3将确定驱动急性肺毒性和信号通路的特定活性氧损伤，从而允许NA诱导的公差。结果将为潜在的减轻药物和生物标志物提供洞察力，以识别和保护处于危险的人。