Air Pollution, Epigenetics and Cardiovascular Health: A Human Intervention Trial

空气污染、表观遗传学和心血管健康：人类干预试验

基本信息

批准号：
8531935
负责人：
Andrea Baccarelli
金额：
$ 20.44万
依托单位：
HARVARD SCHOOL OF PUBLIC HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-16 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8531935
关键词：
Abate Accounting Acute Address Adult Adverse effects Air Air Pollution American American Heart Association Animal Experiments Animal Model Antigens Area Attenuated Betaine Blood Pressure Breathing CD4 Positive T Lymphocytes Caliber Cardiovascular Diseases Cardiovascular system Cessation of life Choline Clinical Cross-Over Studies DNA DNA Methylation Disease Dose Double-Blind Method Endothelium Environment Environmental Exposure Environmental Pollutants Epidemiologic Studies Epigenetic Process Exposure to Folic Acid Gene Expression Genes Genetic Transcription Goals Government Health Heart Helper-Inducer T-Lymphocyte Hospitalization Hour Human In Vitro Individual Inflammation Inflammatory Intervention Intervention Trial Investigation Leukocytes Life Link Lung Mediating Mediation Methionine Methylation Particulate Matter Placebo Control Plasma Pollution Prevention Prevention strategy Preventive Process Public Health Randomized Rattus Research Resources Role Seminal Signal Transduction Simulate Statistical Methods T-Lymphocyte Testing Time Toxic Environmental Substances Translating Translations Up-Regulation Vitamin B6 Work animal data brachial artery cell type cost cytokine environmental stressor exposed human population heart rate variability mRNA Expression methyl group normotensive novel particle public health relevance randomized trial research study response vasoconstriction

项目摘要

DESCRIPTION (provided by applicant): Air pollution is a pervasive environmental threat estimated to cause ~800,000 deaths every year worldwide, mostly due to cardiovascular disease. This proposal addresses a fundamental mechanistic and pharmacologic question about effects of air pollution, which can most effectively be addressed through controlled human exposure experiments: does exposure have epigenetic effects that may have downstream subclinical or clinical consequences, and can adverse effects be safely reduced pharmacologically? Consistent evidence from in- vitro and human studies have shown that exposure to air particulate matter pollution (PM, i.e., fine particles) induces hypomethylation of the DNA, an epigenetic process that can underlie the activation of inflammatory genes and is postulated to link inhalation of PM into the lungs with cardiovascular inflammation and adverse responses. Our goal is to determine whether a pharmacological intervention with methyl-donors (i.e., folic acid, Vitamins B6 & B12, betaine, methionine, and choline) can avert this DNA methylation loss and mitigate the cardiovascular effects induced by PM exposure. We will use experiments of human controlled exposure to PM - which reproduce conditions of exposure similar to those found in real life in urban environments - to conduct a randomized, double-blind, placebo-controlled crossover study. We will test whether pharmacological intervention with methyl-donors attenuates the effects of PM exposure on DNA methylation (Aim 1), mRNA expression & plasma cytokines (Aim 2), and blood pressure, arterial vasoconstriction, endothelial function, and autonomic control of the heart (Aim 3). Our study is poised to be the first human investigation to translate a wealth of animal data showing that methyl-donors can be used to modulate epigenetic states and avert environmental effects. We have a unique opportunity to achieve this goal because we have access to one of the few facilities worldwide for human controlled-exposure studies, as well as to state-of-the-art resources for epigenetics investigations. We will examine DNA methylation and mRNA expression in T-helper cells from human individuals, a cell type with key roles in determining adverse hypertensive and endothelial responses, as shown in several animal models. We will test the effects of methyl-donors on a battery of cardiovascular endpoints that are highly sensitive to PM exposure. We will explore the use of advanced statistical methods for mediation analyses to understand the relationships among PM, DNA methylation, RNA expression, plasma cytokines, and cardiovascular endpoints. The study will be conducted by an investigative team that has conducted seminal work in all of the research areas on which this proposal is built upon, including environmental epigenetics, cardiovascular effects of PM, and human controlled exposure studies.

描述（由申请人提供）：空气污染是一种普遍的环境威胁，估计每年在全球造成约800,000人死亡，主要是由于心血管疾病。该提案解决了关于空气污染影响的基本机械和药理学问题，该问题可以通过受控的人类暴露实验来最有效地解决：暴露是否具有表观遗传效应，可能具有下游次级临床或临床后果，并且可以安全地降低药理学吗？来自体外和人类研究的一致证据表明，暴露于空气颗粒物污染（PM，即细颗粒）会诱导DNA的降低甲基化，这是一种表观遗传学过程，它可以构成炎症基因的激活，并假定将PM吸入到肺部与心血管炎症和不良反应和不良反应和不良反应的肺部。我们的目标是确定用甲基持甲基的药理干预（即叶酸，维生素B6和B12，BETAINE，蛋氨酸和胆碱）是否可以避免这种DNA甲基化损失并减轻由PM暴露引起的心血管效应。我们将使用人类控制接触的PM的实验（这些实验，这些实验会繁殖与在城市环境中现实生活中发现的暴露条件相似的暴露条件，以进行随机，双盲，安慰剂对照的跨界研究。我们将测试用甲基供体的药理学干预是否会减弱PM暴露对DNA甲基化的影响（AIM 1），mRNA表达和血浆细胞因子（AIM 2）和血压，血压，动脉血管收缩，内皮功能，内皮功能和心脏的自主控制（AIM 3）。我们的研究有望成为翻译大量动物数据的第一个人类研究，表明甲基抑制剂可用于调节表观遗传状态并避免环境影响。我们有一个独特的机会来实现这一目标，因为我们可以访问全球范围内为数不多的人类受控研究研究之一，以及用于表观遗传学调查的最新资源。如几种动物模型所示，我们将检查来自人个体的T-Helper细胞中的DNA甲基化和mRNA表达，在确定高血压和内皮反应的不良反应中，具有关键作用，如几种动物模型所示。我们将测试甲基支持对PM暴露高度敏感的心血管终点的影响。我们将探讨使用先进的统计方法用于中介分析，以了解PM，DNA甲基化，RNA表达，血浆细胞因子和心血管终点之间的关系。这项研究将由一个调查团队进行，该团队已在该提案建立的所有研究领域进行了开创性的工作，包括环境表观遗传学，PM的心血管效应以及人类控制的暴露研究。