权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Particulate matter-induced changes in DNA methylome and transcriptome

颗粒物诱导的 DNA 甲基化组和转录组变化

基本信息

批准号：
9098231
负责人：
Gokhan M. Mutlu
金额：
$ 62.85万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9098231
关键词：
Abate Acute Adolescent Adult Affect Age Age-Months Air Pollution Alveolar Cell Alveolar Macrophages Aorta Biological Blood Cells Breathing C57BL/6 Mouse Cardiac Myocytes Cardiopulmonary Cells Cessation of life Chronic DNA DNA Methylation DNA Modification Process Data Development Disease Early identification Elderly Endothelial Cells Environmental Health Epigenetic Process Epithelial Cells Epithelium Exposure to Female Gene Expression Genetic Genetic Transcription Harvest Heart Human Inbred BALB C Mice Individual Leukocytes Life Longevity Lung Mono-S Morbidity - disease rate Mouse Strains Mus Nasal Epithelium Nose Nuclear Particulate Matter Pattern Peripheral Blood Mononuclear Cell Play Pulmonary Heart Disease Repetitive Sequence Risk Role Structure of parenchyma of lung Switch Genes Testing Time Tissue-Specific Gene Expression Tissues age effect aged air filter alveolar type II cell base burden of illness clinically relevant genome-wide global environment in vivo macrophage male methylation pattern methylome monocyte mortality mouse model peripheral blood pregnant premature prenatal exposure public health relevance research study response seal sex transcriptome transcriptome sequencing whole genome

项目摘要

DESCRIPTION (provided by applicant): Particulate matter (PM) air pollution is a global environmental health problem that causes 3.7 million premature deaths annually, representing 6.7% of all deaths worldwide. These deaths are largely due to increased acute cardiopulmonary disease. Although efforts to abate PM levels led to reduction in PM-induced morbidity and mortality, the association between PM and cardiopulmonary disease still persists. There is need for early identification of individuals who are at risk for PM-induced cardiopulmonary disease to reduce the burden of disease further. Exposure to PM is associated with epigenetic modifications of DNA such as DNA methylation (5mC) and hydroxymethylation (5hmC) that regulate gene transcription. Assessment of these epigenetic changes may help with the identification of individuals at risk for development of PM-induced cardiopulmonary diseases. Increasing number of studies demonstrate that PM induces epigenetic changes but the implications of these findings are limited because these studies focused on the methylation patterns of the repetitive elements without detailed analysis of the whole genome. Furthermore, the studies were done in surrogate cells such as blood leukocytes and nasal epithelial cells without any correlation in target tissues. It is not known whether changes in DNA methylation or hydroxymethylation in peripheral blood monocytes can also be found in the target tissue or cell such as lung epithelial cells, alveolar macrophages or aortic endothelial cells. In preliminary studies, we found that PM treatment caused epigenetic changes characterized by reduction in 5mC and increased 5hmC in nasal and lung epithelial cells and alveolar macrophages. In addition to epigenetic changes, PM induced similar expression of some genes and differential expression of others in primary human nasal and lung epithelial cells ex vivo and in a murine model of PM exposure in vivo. PM-induced changes in gene expression and DNA methylation in primary human nasal epithelial cells were different among individuals as well as between males and females suggesting an important role for host-related factors such as genetics, age and sex in influencing the PM-induced responses. Based on our preliminary data, we hypothesized that changes in DNA methylation and hydroxymethylation and the gene expression (RNA-seq) in surrogate cells (nasal epithelial cells and peripheral blood mononuclear cells) can be used to predict those changes in target tissues (lung epithelial cells, and macrophages, heart and aorta). Using a clinically relevant murine model of PM exposure via inhalation, in Aim 1, we will determine the how PM-induced changes in DNA methylome and transcriptome differ in surrogate (nasal epithelium, and peripheral blood monocytes) and target cells (alveolar epithelial cells, macrophages, heart and aorta). In Aim 2, we will determine whether the host related factors (strain, sex and age) affect PM-induced changes in DNA methylome and transcriptome in surrogate and target cells and in Aim 3, we will determine whether the PM-induced changes in DNA methylome and transcriptome in surrogate and target cells persist throughout the lifespan.