Mechanisms of Responses to Diesel Exhaust and Stress

对柴油机尾气和压力的反应机制

基本信息

批准号：
7281239
负责人：
ROBERT John LAUMBACH
金额：
$ 13.26万
依托单位：
UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-23 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7281239
关键词：
Acute Acute-Phase Proteins Address Air Pollutants Air Pollution Alveolar Macrophages Animal Model Animals Antioxidants Aorta Apolipoprotein E Atherosclerosis Binding Blood Blood Circulation Blood Coagulation Factor VII Blood Vessels Breathing Bronchoalveolar Lavage Cardiovascular Diseases Cardiovascular system Cell Adhesion Molecules Cell Count Cells Coronary Coronary artery Corticosterone Corticotropin-Releasing Hormone Cultured Cells Dependence Deposition Development Plans Dichloromethylene Diphosphonate Diesel Exhaust Educational Activities Enzyme-Linked Immunosorbent Assay Epidemiologic Studies Epinephrine Exhibits Exposure to Factor VIII Fibrinogen Goals Heart Hepatic Histology Hormones Hour Human Hyperlipidemia Immunohistochemistry In Situ Hybridization Individual Inflammation Inflammatory Inflammatory Response Inhalation Toxicology Injury Interleukin-1 Interleukin-6 Knockout Mice Laboratories Learning Lipids Lipoproteins Liposomes Liver Lung Measures Mediating Mediator of activation protein Mentorship Messenger RNA Metabolism Modeling Monitor Mus Norepinephrine Numbers Operative Surgical Procedures Organ Outcome Measure Particulate Matter Plasma Plasminogen Activator Inhibitor 1 Plasminogen Inactivators Play Pneumonia Predisposition Procedures Production Proteins Psychoneuroimmunology Research Research Personnel Reverse Transcriptase Polymerase Chain Reaction Risk Role Serum Site Staining method Stains Stress Structure Techniques Testing Thrombophilia Thrombosis Tissues Toxic effect Training Travel Tumor Necrosis Factor-alpha Vascular Diseases Western Blotting Wild Type Mouse air filter atherothrombosis biological adaptation to stress cardiovascular risk factor career concept cytokine exhaust exposed human population lipid transport lung injury macrophage monocyte mortality programs protein expression research and development research study response restraint stress stressor

项目摘要

DESCRIPTION (provided by applicant) The proposed career development and research plans will prepare the candidate to conduct independent research focusing on how the toxic effects of air pollutants may be modified in susceptible individuals, using animal models. Evidence from epidemiological studies indicates that individuals with pre-existing cardiovascular (CV) disease are at increased risk of CV effects from particulate matter air pollution (PM). The research plan will test the hypothesis that the CV effects of PM are mediated by systemic inflammatory responses to local injury and inflammation in the lungs, and that altered macrophage numbers and activity in lung and liver contribute to increased sensitivity of apolipoprotein E-deficient (ApoE-/-) mice to these effects. Moreover, toxic effects will be enhanced by co-exposure to stress. To test this hypothesis, the candidate will use freshly generated diesel exhaust (DE) as a model PM exposure. The first aim is to determine if ApoE-/- mice exhibit increased susceptibility to DE-induced pulmonary and systemic inflammation and prothrombotic activity. ApoE-/- and control mice will be exposed to DE (30-1000 mu/g/m3 PM) or control for 3-6 hours, with outcomes measured at 0-72 hours post-exposure. Markers of inflammation will be assessed in the lung, liver, blood, and blood vessels, including cell counts, cytokine expression, circulating acute phase proteins, and cell adhesion molecules. The second aim is to determine if increases in the sensitivity of ApoE-/- mice to DE are due to increased macrophage numbers and activity in the lung and liver. Dependence of DE-induced effects on macrophages will be tested by selectively depleting these cells using liposomes. The third aim is to determine if stress alters DE-induced inflammatory responses and prothrombotic activity. Inflammation and prothrombotic activity will be analyzed in ApoE-/- and control mice after exposure to DE with and without an acute stressor. Career development plans include mentorship and training in inhalation toxicology and psychoneuroimmunology through supervised research and structured educational activities. Laboratory techniques to be learned include animal exposures, surgery, cell culture, western blotting, ELISA, in situ hybridization, RT-PCR and histochemical procedures. The career development plan will enable the candidate to achieve his overall goal of conducting research that integrates animal studies with human exposure studies. The experimental studies will contribute to elucidating mechanisms underlying CV effects of PM.

描述（由申请人提供）拟议的职业发展和研究计划将使候选人做好准备进行独立研究，重点关注如何使用动物模型改变空气污染物对易感个体的毒性影响。流行病学研究的证据表明，患有心血管 (CV) 疾病的个体因颗粒物空气污染 (PM) 而遭受心血管影响的风险增加。该研究计划将检验以下假设：PM 的 CV 效应是由对肺部局部损伤和炎症的全身炎症反应介导的，并且肺和肝脏中巨噬细胞数量和活性的改变有助于增加载脂蛋白 E 缺陷 (ApoE) 的敏感性。 -/-) 小鼠对这些影响。此外，共同暴露在压力下会增强毒性作用。为了检验这一假设，候选人将使用新产生的柴油废气 (DE) 作为 PM 暴露模型。第一个目的是确定 ApoE-/- 小鼠是否表现出对 DE 诱导的肺部和全身炎症以及血栓前活性的易感性增加。 ApoE-/- 和对照小鼠将暴露于 DE (30-1000 mu/g/m3 PM) 或对照 3-6 小时，并在暴露后 0-72 小时测量结果。将评估肺、肝、血液和血管中的炎症标志物，包括细胞计数、细胞因子表达、循环急性期蛋白和细胞粘附分子。第二个目的是确定 ApoE-/- 小鼠对 DE 敏感性的增加是否是由于肺和肝脏中巨噬细胞数量和活性的增加所致。 DE 诱导效应对巨噬细胞的依赖性将通过使用脂质体选择性地消耗这些细胞来测试。第三个目标是确定压力是否会改变 DE 诱导的炎症反应和促血栓活性。将在暴露于具有和不具有急性应激源的 DE 后，对 ApoE-/- 和对照小鼠的炎症和促血栓活性进行分析。职业发展计划包括通过监督研究和结构化教育活动进行吸入毒理学和心理神经免疫学方面的指导和培训。需要学习的实验室技术包括动物暴露、手术、细胞培养、蛋白质印迹、ELISA、原位杂交、RT-PCR 和组织化学程序。职业发展计划将使候选人能够实现将动物研究与人类暴露研究相结合的研究的总体目标。实验研究将有助于阐明 PM 的 CV 效应的潜在机制。