Epigenetic Variation and Childhood Asthma in Puerto Ricans

波多黎各人的表观遗传变异和儿童哮喘

• 批准号: 9316934
• 负责人: Juan Carlos Celedon
• 金额: $ 77.68万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9316934
• 关键词: ADRB2 gene; Adrenal Cortex Hormones; Affect; Aftercare; Agonist; Applications Grants; Asthma; Biological Markers; Breathing; Bronchodilator Agents; Child; Childhood Asthma; Chronic; Chronic stress; DNA Methylation; Data; Economically Deprived Population; Environment; Epidemiology; Epigenetic Process; Ethnic group; Exposure to; Funding; Gene Expression; Genes; Genetic; Glucocorticoid Receptor; Glucocorticoids; Goals; In Vitro; Interdisciplinary Study; Knowledge; Leukocytes; Mediating; Methods; Methylation; Morbidity - disease rate; NR3C1 gene; Nasal Epithelium; Outcome; Pharmaceutical Preparations; Pharmacology; Prevention approach; Preventive Intervention; Psychopathology; Psychosocial Stress; Puerto Rican; Regulator Genes; Regulatory Pathway; Role; Sexual abuse; Stress; Symptoms; Testing; Therapeutic Intervention; Variant; Violence; beta-2 Adrenergic Receptors; biological adaptation to stress; cohort; common treatment; epigenetic variation; experimental study; genome-wide; high risk population; in vivo; inner city; innovation; member; minority children; novel; parent grant; physical abuse; pituitary adenylate cyclase activating polypeptide; prevent; psychological stressor; receptor; respiratory; response; stressor; therapy resistant; treatment response; underserved minority

Puerto Rican (PR) children share a disproportionate burden from asthma in the U.S. We have demonstrated that in PR children, a variety of psychological stressors -including physical or sexual abuse, exposure to violence, and parental psychopathology- are associated with worse asthma outcomes. Puerto Rican children also have reduced response to bronchodilators (short-acting inhaled β2-agonists, the most commonly used medication for asthma worldwide). We have recently shown that high child stress is associated with reduced response to short-acting inhaled β2-agonists (bronchodilator response or BDR) in PR children with asthma, and our preliminary results also implicate genetic and epigenetic (DNA methylation) variation in genes involved in stress responses (e.g., ADCYAP1R1) on asthma and BDR. Moreover, external in vitro experiments show that high stress leads to reduced expression of the genes for the β2-adrenergic receptor (ADRB2) and the glucocorticoid receptor (NR3C1) in white blood cells of children with asthma. While it is known that stress reduces BDR, it is not known whether this can be prevented by treatment with inhaled corticosteroids (ICS), or whether stress reduces response to ICS in vivo. Moreover, we have very limited knowledge of the genetic or epigenetic mechanisms underlying treatment resistance in stressed children. Lack of such knowledge is an important problem, because, without it, gaining the ability to prevent or treat stress-induced asthma morbidity in underserved children is highly unlikely. On the basis of our novel preliminary results, we hypothesize that chronic stress reduces response to inhaled corticosteroids (ICS) and BDR in PR children with asthma, and that these effects are mediated by altered methylation of genes regulating responses to stress, corticosteroids and BDR. To test this hypothesis, we will first determine whether increased stress leads to reduced response to ICS or BDR (even after treatment with ICS) in 300 PR children with asthma (Sp. Aim 1). We will then test for association between high child stress and genome-wide DNA methylation in respiratory (nasal) epithelium in 550 Puerto Rican children with asthma (Sp. Aim 2). Next, we will examine whether methylation changes in the top 100 genes identified in Aim 2 are associated with response to ICS or BDR in 300 to 550 PR children with asthma (Sp. aim 3a). Finally, we will assess the effects of methylation changes identified in Aim 3a on gene expression (Sp. Aim 3b). This proposal should determine whether and how psychosocial stress leads to reduced response to common treatments for asthma control (ICS) and relief of asthma symptoms (short-acting inhaled β2-agonists) in a high-risk group (Puerto Rican children). To achieve this goal, we have assembled an outstanding multidisciplinary research team.

波多黎各人（PR）儿童在美国有哮喘的不成比例的伯宁 在公关儿童中 和父母的心理病理学 - 与哮喘结局较差有关。波多黎各儿童也有 减少对支气管扩张剂的响应（短期掺入Beta2-agenists，是最常用的药物 全球哮喘）。我们最近表明，高儿童压力与对 PR儿童哮喘儿童的短效β2-激动剂（支气管扩张剂反应或BDR），我们的 初步结果还暗示了与应激有关的基因的遗传和表观遗传学（DNA甲基化）变异 哮喘和BDR上的反应（例如ADCYAP1R1）。此外，外部体外实验表明高 应力导致β2-肾上腺素能受体（ADRB2）和糖皮质激素的基因表达降低 哮喘儿童的白细胞中的受体（NR3C1）。虽然已知压力减少了BDR，但它是 尚不知道是否可以通过遗传性皮质类固醇（IC）或压力来阻止这种情况 减少对体内IC的反应。此外，我们对遗传或表观遗传学的了解非常有限 压力儿童的耐药性机制。缺乏这种知识是重要的 问题，因为没有它，可以获得预防或治疗压力引起的哮喘发病率的能力 服务不足的孩子极不可能。根据我们新颖的初步结果，我们假设 慢性应激减少了患有哮喘儿童的遗传性皮质类固醇（ICS）和BDR的反应，并且 这些作用是通过调节压力，皮质类固醇和压力反应的基因甲基化改变来介导的。 BDR。为了检验这一假设，我们将首先确定增加的压力是否导致对 ICS或BDR（即使在ICS治疗后）在300名PR哮喘儿童中（Sp。AIM1）。然后我们将测试 高儿童应激与全基因组DNA甲基化在呼吸道（鼻）上皮之间的关联 550波多黎各哮喘儿童（Sp。AIM2）。接下来，我们将研究甲基化是否在 AIM 2中确定的前100个基因与300至550名PR儿童的ICS或BDR的反应有关 哮喘（Sp。AIM3A）。最后，我们将评估AIM 3A中鉴定出的甲基化变化对基因的影响 表达式（sp。AIM3B）。该提议应确定社会心理压力是否以及如何导致 减少对哮喘控制（ICS）常见治疗的反应和哮喘症状的缓解（短期作用 在高风险群体（波多黎各儿童）中吸入β2激动剂）。为了实现这一目标，我们组装了一个 出色的多学科研究团队。