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存在的环境威胁，估计每年导致全世界约 800,000 人死亡，其中大部分是由于心血管疾病。该提案解决了有关空气污染影响的基本机制和药理学问题，该问题可以通过受控人体暴露实验最有效地解决：暴露是否具有可能产生下游亚临床或临床后果的表观遗传效应，以及可以通过药理学安全地减少不良反应吗？来自体外和人体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 低甲基化，这是一种表观遗传过程，可能是炎症基因激活的基础，并被认为与吸入PM进入肺部会引起心血管炎症和不良反应。我们的目标是确定甲基供体（即叶酸、维生素 B6 和 B12、甜菜碱、蛋氨酸和胆碱）的药物干预是否可以避免这种 DNA 甲基化损失并减轻 PM 暴露引起的心血管影响。我们将利用人体受控接触 PM 的实验（重现与城市环境中现实生活中发现的接触条件类似的接触条件）来进行随机、双盲、安慰剂对照的交叉研究。我们将测试甲基供体的药物干预是否会减弱 PM 暴露对 DNA 甲基化（目标 1）、mRNA 表达和血浆细胞因子（目标 2）以及血压、动脉血管收缩、内皮功能和心脏自主控制的影响（目标 3）。我们的研究有望成为第一个转化大量动物数据的人类研究，表明甲基供体可用于调节表观遗传状态并避免环境影响。我们拥有实现这一目标的独特机会，因为我们可以使用全球为数不多的用于人类受控暴露研究的设施之一，以及用于表观遗传学研究的最先进的资源。我们将检查人类 T 辅助细胞中的 DNA 甲基化和 mRNA 表达，如几种动物模型所示，辅助性 T 细胞是一种在确定不良高血压和内皮反应中发挥关键作用的细胞类型。我们将测试甲基供体对一系列对 PM 暴露高度敏感的心血管终点的影响。我们将探索使用先进的统计方法进行中介分析，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小组进行，该小组在该提案所依据的所有研究领域都进行了开创性的工作，包括环境表观遗传学、PM 的心血管影响以及人类受控暴露研究。