Exposure to violence, epigenetic variation, and asthma in Puerto Rican children

波多黎各儿童遭受暴力、表观遗传变异和哮喘

基本信息

批准号：
9385085
负责人：
Juan Carlos Celedon
金额：
$ 30.17万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-02 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9385085
关键词：
Address Adenylate Cyclase Affect Asthma Behavioral Biological Markers Bronchodilator Agents Child Childhood Childhood Asthma Chronic Communities Crime DNA Methylation Data Disease Economically Deprived Population Emergency department visit Environment Epidemiology Epigenetic Process Epithelial Cells Ethnic group Exposure to Gene Expression Gene Proteins Genes Genetic Goals Health Policy Health Professional Health Promotion Hospitalization Human Immune response Individual Interdisciplinary Study Knowledge Law Enforcement Link Lung diseases Measures Mental Health Methods Methylation Morbidity - disease rate Nasal Epithelium Neurosecretory Systems Outcome Pharmacology Prevention Prevention approach Preventive Intervention Psychopathology Public Health Puerto Rican Regulatory Pathway Reporting Respiratory physiology Risk Severities Sexual abuse Stress Testing Therapeutic Intervention United States Violence epigenetic variation genetic variant genome-wide gun control laws high risk innovation member minority children novel physical abuse pituitary adenylate cyclase activating polypeptide polypeptide prevent psychological stressor psychosocial receptor respiratory response stressor underserved minority

项目摘要

Puerto Rican children share a disproportionate burden from asthma in the U.S. We have demonstrated that in Puerto Rican children, a variety of psychological stressors -including physical or sexual abuse, parental psychopathology, and exposure to violence- are associated with asthma and worse asthma outcomes. In particular, we have shown that exposure to violence is associated with childhood asthma in Puerto Ricans. Moreover, we have reported that exposure to violence is associated with DNA methylation of the gene for the pituitary adenylate cyclase activating polypeptide 1 type 1 receptor (ADCYAP1R1), and that such methylation and a genetic variant in ADCYAP1R1 are each associated with asthma in Puerto Rican children. While exposure to violence has been implicated in asthma and increased morbidity from asthma in children, we have very limited knowledge about the epigenetic mechanisms underlying this link. Lack of such knowledge is an important problem, because, without it, gaining the ability to prevent or treat asthma in underserved children exposed to violence is highly unlikely. On the basis of our novel preliminary findings, we hypothesize that exposure to violence increases the risk of asthma and asthma morbidity through altered methylation of genes regulating behavioral, autonomic, neuroendocrine and immunologic responses to stress. To test this hypothesis, we will first test for association between exposure to violence and genome-wide DNA methylation changes in respiratory (nasal) epithelium in 500 Puerto Rican children (Sp. Aim 1). Next, we will examine whether methylation changes in the top genes identified in Aim 1 are associated with asthma and measures of worse asthma severity or control (severe asthma exacerbations, reduced lung function, and reduced bronchodilator response) in 250 to 500 Puerto Rican children (Sp. Aim 2). Finally, we will assess the effects of methylation changes in the genes identified in Aim 2 on gene expression in nasal epithelium of Puerto Rican children (Sp. Aim 3a), as well as on gene expression and protein abundance in primary human bronchial epithelial cells (Sp. Aim 3b). This proposal should determine how exposure to violence leads to increased risk of asthma and asthma morbidity in underserved minority children, such as Puerto Ricans. To achieve this goal, we have assembled an outstanding multidisciplinary research team.

在美国，波多黎各儿童承受着不成比例的哮喘负担。我们已经证明，在波多黎各儿童面临各种心理压力 - 包括身体虐待或性虐待、父母的虐待精神病理学和接触暴力与哮喘和更严重的哮喘结果相关。在特别是，我们已经证明，波多黎各人遭受暴力与儿童哮喘有关。此外，我们还报告称，接触暴力与该基因的 DNA 甲基化有关。垂体腺苷酸环化酶激活多肽 1 1 型受体 (ADCYAP1R1)，并且这种甲基化 ADCYAP1R1 的基因变异均与波多黎各儿童的哮喘有关。尽管接触暴力与哮喘有关，并且儿童哮喘发病率增加，我们已关于这种联系背后的表观遗传机制的知识非常有限。缺乏这样的知识是一个重要的问题，因为如果没有它，就无法获得预防或治疗服务不足的儿童的哮喘的能力遭受暴力的可能性极小。根据我们新颖的初步发现，我们假设接触暴力会通过基因甲基化的改变增加哮喘风险和哮喘发病率调节对压力的行为、自主、神经内分泌和免疫反应。为了检验这个假设，我们将首先测试暴露于暴力和基因组 DNA 甲基化变化之间的关联 500 名波多黎各儿童的呼吸道（鼻）上皮细胞（Sp. Aim 1）。接下来，我们将检查是否目标 1 中确定的主要基因的甲基化变化与哮喘和更糟糕的症状相关哮喘严重程度或控制（哮喘严重发作、肺功能下降和支气管扩张剂减少）响应）在 250 至 500 名波多黎各儿童中（Sp. 目标 2）。最后，我们将评估甲基化的影响目标 2 中确定的基因变化对波多黎各儿童鼻上皮基因表达的影响 (Sp. 目标 3a)，以及原代人支气管上皮细胞 (Sp. 目标 3b)。该提案应确定接触暴力如何导致哮喘和哮喘风险增加服务不足的少数族裔儿童（例如波多黎各人）的哮喘发病率。为了实现这一目标，我们有组建了一支优秀的多学科研究团队。