Project 1: Vascular Response to Diesel Exhaust in Humans

项目 1：人体对柴油机尾气的血管反应

基本信息

批准号：
8278529
负责人：
Joel Daniel Kaufman
金额：
$ 32.35万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8278529
关键词：
Acetylcysteine Acute Air Pollutants Air Pollution Angiotensin II Angiotensin Receptor Animal Model Animals Antioxidants Attenuated Behavior Biological Markers Blood Vessels Breathing Cardiovascular Diseases Cell Culture Techniques Cell model Cells Ceruloplasmin Clinical Code Coronary artery Diesel Exhaust Disease Endothelin-1 Endothelium Epidemiologic Studies Equilibrium Event Exposure to Genes Genetic Polymorphism Genetic Predisposition to Disease Genetic Transcription Heat shock proteins Hour Human In Vitro Individual Inflammation Mediators Interleukin-6 Kinetics Link Losartan Measurable Measures Mediator of activation protein Modeling Molecular Molecular Profiling Myocardial Infarction Myocardial Ischemia Oxidative Stress Particulate Particulate Matter Pathway interactions Peripheral Blood Mononuclear Cell Physiological Plasma Preproendothelin Prevention Production RNA Receptor, Angiotensin, Type 1 Renin-Angiotensin System Resolution Sampling Scientist Series Smooth Muscle Smooth Muscle Myocytes Supplementation Testing Therapeutic Time Tissue Sample Tissues Toxicogenomics Ultrasonography Urine Variant Work air filter ascorbate base brachial artery constriction cytokine exposed human population free radical oxygen gene therapy genetic variant human subject human tissue in vitro Model insight intervention effect mouse model receptor repository research study response time use trafficking vasoconstriction

项目摘要

Air pollution exposures are associated with ischemic heart diseases including myocardial infarction. Recent observations demonstrate that air pollutants, including fine particulate and diesel exhaust (DE), trigger increased arterial reactivity and vasoconstriction in both human and animal models. We will use inhaled DE to study vascular effects in a clinical setting. The hypothesis is that DE exerts vascular effects via oxidative stress, through one of the well-established mechanisms controlling endothelium and smooth muscle in conductance vessels, altering the balance of constriction and dilation. First, in human subjects, we will test whether the observed vasoconstrictive response in the brachial artery (using ultrasound) following DE exposure is blunted with antioxidant administration, and heightened in individuals with genetic susceptibility to angiotensin II (AT., receptor variant AGTR1 A1166C)). The associated DE-induced changes in soluble mediators such as IL-6, and markers of endothelial activation such as endothelin-1 will be also be determined. Second, we will establish a time course for events occurring with regard to soluble mediators, endothelial activation, and vasoconstriction, using serial studies of each parameter, as well as serial measures of gene transcription in peripheral blood mononuclear cells, and determine if specific effects are blocked by the AT! receptor blocker losartan. We will also determine if DE's vasoconstrictive effects are increased in subjects with a common SNP variant in the gene coding for preproendothelin, a variation which is already associated with hypertensive responses. Third, we will closely integrate our studies with other projects in the DISCOVER Center. We will determine if hypotheses explored in animal and in vitro models can be tested in our human studies. For example, we will determine if DE increases plasma levels of ceruloplasmin and Heat Shock Protein. We will also create a repository of paired human samples exposed to DE and FA, for additional analyses and for incubation with human cells in culture studies. The studies exploit a partnership between clinical and basic scientists to explore the key mechanisms underlying this environmentally-induced disease. We will derive an understanding of the causes of air pollutant-related cardiovascular disease. This information is needed to develop prevention and therapeutic strategies.

空气污染暴露与包括心肌梗塞在内的缺血性心脏病有关。最近的观察表明，空气污染物，包括细颗粒物和柴油机尾气 (DE)，会引发在人类和动物模型中增加动脉反应性和血管收缩。我们将使用吸入DE 研究临床环境中的血管效应。假设 DE 通过氧化作用发挥血管作用压力，通过控制内皮和平滑肌的成熟机制之一传导血管，改变收缩和扩张的平衡。首先，在人类受试者中，我们将测试观察到的肱动脉血管收缩反应是否（使用超声波）DE暴露后，抗氧化剂的施用会减弱，并且在对血管紧张素 II（AT.，受体变体 AGTR1 A1166C）具有遗传易感性的个体。这 DE 诱导的可溶性介质（例如 IL-6）和内皮激活标志物的变化例如内皮素-1也将被测定。其次，我们将为与可溶性介质、内皮细胞有关的事件建立一个时间进程。使用每个参数的系列研究以及基因的系列测量来激活和血管收缩外周血单核细胞中的转录，并确定特定效应是否被 AT 阻断！受体阻滞剂氯沙坦。我们还将确定 DE 的血管收缩作用是否在受试者中增加前内皮素原编码基因中存在常见的 SNP 变异，这种变异已经与伴有高血压反应。第三，我们将把我们的研究与DISCOVER中心的其他项目紧密结合起来。我们将确定是否在动物和体外模型中探索的假设可以在我们的人体研究中得到检验。例如，我们将确定 DE 是否会增加血浆铜蓝蛋白和热休克蛋白的水平。我们还将创建一个暴露于 DE 和 FA 的配对人类样本储存库，用于额外分析和孵化培养研究中的人类细胞。这些研究利用临床和基础科学家之间的合作来探索关键机制这种环境诱发的疾病的根源。我们将了解空气的成因污染物相关的心血管疾病。需要这些信息来制定预防和治疗措施策略。