MOUSE BIOMARKER DISCOVERY AND VALIDATION STUDIES

小鼠生物标志物的发现和验证研究

• 批准号: 7637340
• 负责人: RICHARD A CORLEY
• 金额: $ 48.76万
• 依托单位: BATTELLE PACIFIC NORTHWEST LABORATORIES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-10 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7637340
• 关键词: Adult; Animals; Antibodies; Antioxidants; Benchmarking; Biological; Biological Assay; Biological Markers; Biological Monitoring; Biosensor; Body Fluids; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Carbon Tetrachloride; Cardiovascular system; Child; Chronic; Clinic; Complement; Cotinine; Count; Custom; Data; Databases; Development; Endotoxins; Environmental Risk Factor; Enzyme-Linked Immunosorbent Assay; Evaluation; Exposure to; Gene Proteins; Generations; Generic Drugs; Genome; Human; Individual; Inflammation; Inflammatory; Inhalation Toxicology; Invasive; Laboratories; Lipopolysaccharides; Liquid substance; Liver; Lung; Lung diseases; Mainstreaming; Mass Spectrum Analysis; Measurement; Measures; Monitor; Morbidity - disease rate; Mus; Nicotine; Obese Mice; Obesity; Organ; Overweight; Oxidants; Oxidative Stress; Paraquat; Pathway interactions; Peptides; Plasma; Plasma Cells; Population; Post-Translational Protein Processing; Predisposition; Proteins; Proteomics; Reaction; Reactive Nitrogen Species; Reactive Oxygen Species; Reagent; Reproducibility; Research; Risk Factors; Saliva; Sampling; Smoke; Smoking; Standards of Weights and Measures; Structure of parenchyma of lung; System; Teenagers; Testing; Tissues; Tobacco smoke; Toxic Environmental Substances; Validation; base; cancer risk; chemokine; cigarette smoking; comparative; cytokine; design; detector; environmental chemical; environmental stressor; experience; human morbidity; human study; mortality; research study; response; saliva analysis; sensor; smoke inhalation; tandem mass spectrometry; transcriptomics; validation studies

Two of the most important preventable risk factors for human morbidity and mortality are exposure to cigarette smoke and obesity, each raising the risk of cancer, cardiovascular, or respiratory disease. Oxidative stress may be the unifying mechanism underlying the development of co-morbidities of smoking and obesity and for the interaction of these risk factors with other environmental toxicants and the genome. Thus, this project will build upon our Laboratory's experience in sensor development, tobacco smoke inhalation toxicology, transcriptomics, and proteomics, to conduct controlled exposure studies in normal and obese mice to materials that produce inflammation and/or oxidative stress. Studies will be conducted with cigarette smoke (mainstream vs. sidestream) to complement the human studies described in Project 1, followed by exposures to the inflammatory bacterial agent, endotoxin (lipopolysaccharide, LPS), and the lung and liver oxidants, paraquat and carbon tetrachloride, to test mode-of-action and tissue-dependent responses. The mouse studies will facilitate discovery, verification, refinement and validation of candidate protein biomarkers of oxidative stress and inflammation using mass spectrometry proteomic approaches that will be added to PNNL's two proposed biosensor platforms-a laboratory-based sandwich ELISA microarray capable of quantitating dozens of protein biomarkers (Core B) and an in-clinic deployable nanoparticlebased, multiplexed immunochromatographic electrochemical biosensor capable of quantitating multiple biomarkers of exposure (e.g. an environmental chemical and/or its metabolites) and response (protein biomarkers of oxidative stress and inflammation) (Project 3). The mouse studies will enable comparisons of responses in target tissues, which cannot be done in humans, with biomarkers of oxidative stress/inflammation that can be quantitated in samples collected by progressively less invasive approaches (e.g. bronchoalveolar lavage fluid, plasma, saliva) to facilitate biosensor platform deployment in large scale human biomonitoring studies. Furthermore, this project provides parallel examination of the responses in normal mice with those in obese mice to identify key biological pathways that define the relationships between the environmental factors contributing to susceptibility, thereby creating an important database of global gene and protein profiling to perform mouse to human extrapolations.

人类发病率和死亡率的两个最重要的可预防风险因素是接触 吸烟和肥胖都会增加患癌症、心血管或呼吸道疾病的风险。 氧化应激可能是吸烟并发症发生的统一机制 和肥胖以及这些危险因素与其他环境毒物和基因组的相互作用。 因此，该项目将建立在我们实验室在传感器开发、烟草烟雾等方面的经验基础上 吸入毒理学、转录组学和蛋白质组学，在正常和 肥胖小鼠对产生炎症和/或氧化应激的物质。研究将与 香烟烟雾（主流与侧流）以补充项目 1 中描述的人体研究， 随后暴露于炎症细菌、内毒素（脂多糖，LPS）和肺部 和肝脏氧化剂、百草枯和四氯化碳，以测试作用模式和组织依赖性 回应。小鼠研究将促进候选药物的发现、验证、完善和验证 使用质谱蛋白质组学方法确定氧化应激和炎症的蛋白质生物标志物 将被添加到 PNNL 提议的两个生物传感器平台中——基于实验室的夹心 ELISA 微阵列 能够定量数十种蛋白质生物标志物（核心 B）和基于临床可部署纳米颗粒的、 多重免疫色谱电化学生物传感器能够定量多种 暴露的生物标志物（例如环境化学物质和/或其代谢物）和反应（蛋白质 氧化应激和炎症的生物标志物）（项目 3）。小鼠研究将能够比较 使用氧化生物标志物在靶组织中产生反应，而这在人类中是无法完成的 可以通过逐渐侵入性较小的方法收集的样本中对压力/炎症进行定量 （例如支气管肺泡灌洗液、血浆、唾液）以促进生物传感器平台的大规模部署 人体生物监测研究。此外，该项目还对以下问题的答复进行并行审查： 将正常小鼠与肥胖小鼠进行比较，以确定定义这些关系的关键生物学途径 影响易感性的环境因素之间的关系，从而创建一个重要的数据库 进行小鼠到人类外推的全局基因和蛋白质分析。