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

• 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
• 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

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，波多黎各儿童因哮喘分担了不成比例的负担。我们在 波多黎各儿童，各种心理压力源--包括身体或性虐待，父母 精神病理学和接触暴力--与哮喘和更糟糕的哮喘结局有关。在……里面 具体地说，我们已经表明，在波多黎各人中，接触暴力与儿童哮喘有关。 此外，我们已经报道，暴露在暴力环境中与 垂体腺苷环化酶激活多肽1型受体(ADCYAP1R1)及其甲基化 ADCYAP1R1的一个基因变异都与波多黎各儿童的哮喘有关。而当 接触暴力与哮喘有关，并增加了儿童哮喘的发病率，我们 对这种联系背后的表观遗传机制的了解非常有限。缺乏这样的知识是一种 这是一个重要的问题，因为如果没有它，就会获得预防或治疗服务不足儿童哮喘的能力 暴露在暴力之下的可能性极小。根据我们新的初步发现，我们假设 暴露在暴力环境中会通过基因甲基化改变增加哮喘和哮喘发病率的风险 调节应激的行为、自主神经、神经内分泌和免疫反应。为了检验这一假设， 我们将首先测试暴露于暴力与全基因组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(SP。目标1)。接下来，我们将考察一下 目标1中发现的顶级基因的甲基化变化与哮喘和病情恶化的措施有关 哮喘严重程度或控制(严重哮喘加重、肺功能下降和支气管扩张剂减少 回答)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 波多黎各儿童鼻上皮中AIM 2基因表达的变化(Sp. Aim 3a)，以及原代人支气管上皮细胞的基因表达和蛋白丰度。 目标3b)。这项建议应该确定暴露在暴力环境中如何导致哮喘风险增加以及 在服务不足的少数族裔儿童，如波多黎各人中，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。