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Maternal exposures modify offspring allergic airway disease risk via epigenetic reprogramming

母亲暴露通过表观遗传重编程改变后代过敏性气道疾病风险

基本信息

批准号：
10383134
负责人：
Jairus C Pulczinski
金额：
$ 4.6万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10383134
关键词：
Adult Affect Air Pollution Allergens Allergic Aromatic Polycyclic Hydrocarbons Asthma Birth Candidate Disease Gene Cell Count Child Childhood Asthma Chronic Chronic Disease Complex Conceptions DNA Methylation Data Development Diet Disease Elderly Embryo Environment Environmental Risk Factor Epigenetic Process Etiology Exposure to Female Fetal Development Fetal Growth Fetal Lung Fetus Folic Acid Gene Expression Genes Growth Growth and Development function Health Human Immune response Individual Inflammation Inflammatory Intake Interferon Type II Knowledge Lactation Life Cycle Stages Link Liquid substance Lung Maternal Exposure Maternal Health Maternal-Fetal Exchange Measures Mediating Mediator of activation protein Messenger RNA Methylation Molecular Mothers Mus Neural Tube Defects Nutrient Nutritional status Oxidative Stress Pathogenesis Perinatal Perinatal Exposure Phenotype Physiological Placenta Play Predisposition Pregnancy Pregnant Women Prevalence Pyroglyphidae RNA Research Risk Role Sampling Structure Structure of parenchyma of lung Testing Tissue Sample Transcript Umbilical Cord Blood Work airway hyperresponsiveness allergic airway disease cytokine design disorder risk environmental tobacco smoke epidemiology study epigenetic marker epigenetic regulation epigenome fetal folic acid supplementation genome-wide immune function indoor allergen insight lung development lung injury lung volume maternal stress metabolic profile methylation pattern methylome offspring postnatal prenatal exposure prevent promoter pulmonary function response

项目摘要

PROJECT SUMMARY Asthma is the most common chronic disease among children in the US and globally, and its prevalence is increasing. In utero exposures have been shown to alter offspring asthma risk, but the mechanisms governing this effect are unclear. Compelling data has demonstrated that the structure and function of the fetal lung may be altered by maternal exposures and thus predisposed to asthma before birth. Our previous work has demonstrated that prenatal exposure to house dust mite (HDM) extract, a ubiquitous indoor allergen, increases offspring lung reactivity in the absence of a secondary exposure in mice. In offspring exposed prenatally and then later exposed in adulthood, airway reactivity was further increased. These changes were accompanied by genome wide and gene-specific changes in DNA methylation in the lung, implying that epigenetic alterations may play a role in this phenomenon. The objective of this research is to investigate the effects of maternal exposures on offspring lung health throughout development. We hypothesize that maternal allergen exposure alters the fetal methylome, leading to dysregulated fetal lung growth and development, resulting in increased airway hyperresponsiveness in later life, and that concurrent exposure with a methyl donor enriched diet may alter the effect of maternal allergen exposure on offspring. This phenomenon will be investigated via two specific aims. Specific aim 1: examine the effects of maternal house dust mite and/or methyl-enriched diet exposure on lung function and epigenetic markers of lung growth, development, and defense from the fetal lung to the adult lung. Additionally, we hypothesize that the effects of maternal exposures on the fetus are mediated by the placenta, thus placental dysregulation induced by maternal exposures can result in altered fetal growth and function. To investigate this, we propose Specific aim 2: investigate the influence of the maternal/fetal interface on fetal epigenetic regulation of fetal lung development in offspring. We will examine the effect of maternal house dust mite exposure on maternal oxidative stress, inflammation, and placental function. The completion of these aims will offer insight into how maternal exposures alter offspring asthma risk, including whether allergen exposure directly target and modify lung development, and/or indirectly affect offspring asthma risk by altering placenta functions.

项目总结