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（由申请人证明）：nachthalene（NA）是一种急性呼吸有毒物质和潜在的人类肺癌。公共卫生，但涉及肺部毒品的经济成本。 NA诱导的肺毒和耐受性的炎症细胞雌激素的产生；生物激活步骤允许参与者之间的合作，共享动物模型，独特的技能（例如气道解剖），分子，细胞和基因毒性的观点。 Topread的肿瘤变化和最终的致癌作用将产生一种新型的小鼠模型，并在NA诱导的超声音和耐受性中建立巨噬细胞的作用，这是在增生结节的发展之前。 ND生物标志物用于未来的翻译研究，以识别和保护处于危险的人。