HUMAN BIOMARKER DISCOVERY AND VALIDATION STUDIES

人类生物标志物的发现和验证研究

• 批准号: 7637339
• 负责人: Joel G Pounds
• 金额: $ 23.81万
• 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/7637339
• 关键词: Adult; Age-Years; Antibodies; Arthritis; Arts; Benchmarking; Biological Assay; Biological Markers; Biology; Biosensor; Body mass index; Breathing; Centers for Disease Control and Prevention (U.S.); Cessation of life; Child; Cholesterol; Chronic; Chronic Disease; Chronic Obstructive Airway Disease; Clinic; Collaborations; Comorbidity; Complex; Cotinine; Custom; Data; Databases; Development; Disease; Enzyme-Linked Immunosorbent Assay; Evaluation; Exposure to; Gall Bladder Diseases; Generic Drugs; Genes; Genome; Goals; Heart Diseases; High Blood Pressure; Human; Hypertension; Individual; Inflammation; Inflammatory; Inflammatory Response; Laboratories; Measurement; Measures; Modification; Monitor; Morbidity - disease rate; Mus; Nitrogen; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Outcome; Overweight; Oxidative Stress; Participant; Pathway interactions; Peptides; Plasma; Plasma Proteins; Population; Predisposition; Proteins; Proteomics; Reaction; Reactive Oxygen Species; Reagent; Reproducibility; Risk; Risk Factors; Sampling; Side; Sleep disturbances; Smoker; Smoking; Source; Specificity; Standards of Weights and Measures; Stimulus; Stream; Stress; Stroke; System; Teenagers; Testing; Tobacco use; Toxic Environmental Substances; United States; United States National Center for Health Statistics; Validation; aged; base; cancer type; cigarette smoking; cohort; cytokine; design; detector; environmental stressor; human disease; human morbidity; mortality; nanoparticle; non-smoker; programs; response; sensor; stressor; tandem mass spectrometry; validation studies

The ultimate goal of the Exposure Biology Program is to understand the development and progression of complex disease by accurately, and quantitatively assessing the individual's exposure to environmental stressors and the individual's responses to these stressors. Two of the most important risk factors for human morbidity and mortality are exposure to cigarette smoke and obesity. Smoking and obesity are each associated with systemic chronic inflammatory and oxidative stress. There is increasing evidence that the oxidative stress resulting from chronic inflammatory stimuli is the unifying mechanism underlying the development of co-morbidities in cigarette smoke and obesity and for the interaction of these risk factors with other environmental toxicants and the genome. We hypothesize that reactive nitrogen and reactive oxygen species (RNS/ROS) modified proteins in plasma will provide important biomarkers for exposure to cigarette smoke, presence of obesity, and the combined response. The overarching objective for Project 1 is to identify, verify, and validate plasma protein biomarkers of oxidative stress in a human population through four aims: Aim 1. Identify RNS/ROS-modified peptides as candidate biomarkers in human plasma using MS/MS. Aim 2 will Verify RNS/ROS-modified peptides as specific biosignatures in 120 human plasma samples by data-directed MS and FTICR-MS (Core A). Aim 3. Validate RNS/ROS-modified proteins for use as specific biomarkers using custom-designed sandwich ELISA microarrays (Core B). The validation will include development and evaluation of antibody reagents and assay reproducibility and sensitivity (Core B). The selection of proteins for validation will be informed by Project 2. Aim 4. Test in the laboratory and in the clinic, a detector system for exposure and for both specific and general markers of RNS/ROS response (with Project 3). The sensor system is nanoparticle-based multiplexed Immunochromatographic / Electrochemical Biosensor (IEB) that will support the measurement of markers for exposure (cotinine) and specific RNS/RNS modified proteins and generic response markers of oxidative stress and chronic inflammation on a single platform. Project 1 will apply state-of-the-art proteomic analysis of human plasma samples from robust, well characterized cohort to provide NIEHS a database of candidate biomarkers, and reagents for selected markers for exposure to cigarette smoke, presence of obesity, and the combined effect. The biomarkers will be tested and validated a cohort containing 500 humans and informed by parallel studies in mice, and deployed on robust, in-clinic deployable nanoparticle-based sensors.

暴露生物学项目的最终目标是了解人类免疫缺陷的发展和进展 通过准确、定量地评估个人在环境中的暴露程度，从而获得复杂的疾病 压力源和个体对这些压力源的反应。人类面临的两个最重要的风险因素 发病率和死亡率与吸烟和肥胖有关。吸烟和肥胖各有不同 与全身性慢性炎症和氧化应激有关。越来越多的证据表明， 慢性炎症刺激引起的氧化应激是导致 吸烟与肥胖共病的发展以及这些危险因素与 其他环境毒物和基因组。我们假设活性氮和活性氧 血浆中物种(RNS/ROS)修饰蛋白将为香烟暴露提供重要的生物标志物 吸烟，肥胖的存在，以及联合反应。项目1的总体目标是 通过以下方法确定、验证和验证人类群体中氧化应激的血浆蛋白生物标志物 四个目标：目标1.用RNS/ROS修饰多肽作为人血浆中的候选生物标志物 MS/MS Aim 2将在120人血浆中验证RNS/ROS修饰的多肽是特定的生物特征 样品通过数据定向MS和FTICR-MS(核心A)。目标3.验证RNS/ROS修饰的蛋白质是否可用 作为特定的生物标志物，使用定制设计的夹心ELISA微阵列(核心B)。验证将 包括抗体试剂的开发和评估以及检测的重复性和灵敏度(核心B)。 用于验证的蛋白质的选择将由项目2通知。目标4.在实验室和在 临床，用于暴露以及RNS/ROS反应的特异性和一般性标志物的检测系统(具有 项目3)。传感器系统是基于纳米颗粒的多重免疫层析/电化学 生物传感器(IEB)，支持测量暴露标志物(可替宁)和特定的RNS/RNS 氧化应激和慢性炎症的修饰蛋白质和通用反应标记物 站台。项目1将应用最先进的蛋白质组分析来自Robust，Well的人类血浆样本 特征队列，为NIEHS提供候选生物标记物的数据库，以及选定的试剂 暴露在香烟烟雾中的标志，肥胖的存在，以及两者的综合影响。生物标志物将 在包含500人的队列中进行测试和验证，并通过小鼠的平行研究获得信息，以及 部署在坚固的临床可部署纳米颗粒传感器上。