Mouse allergen intervention and DNA methylation of asthma regulatory genes

小鼠过敏原干预和哮喘调节基因的 DNA 甲基化

基本信息

批准号：
8350980
负责人：
RACHEL L MILLER
金额：
$ 26.68万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8350980
关键词：
17 year old Address Allergen Immunotherapy Allergens Asthma Biological Biological Markers Boxing Cells Child Clinic Clinic Visits Clinical DNA Methylation Data Disease Dust Education Epigenetic Process Event Exhalation Exposure to Funding Future Gene Expression Genes Genetic Transcription Home environment Home visitation House Call Immune System Diseases Immunotherapy Interferons Intervention Intervention Studies Laboratories Life Measures Mediating Methylation Molecular Mus National Institute of Allergy and Infectious Disease Nitric Oxide Pathway interactions Patients Principal Investigator Production Public Health Randomized Randomized Controlled Trials Recommendation Regulation Regulator Genes Research Screening procedure Specimen Symptoms T cell regulation Telephone Testing Toxic Environmental Substances Translations Treatment Efficacy active method airway inflammation allergic airway disease arginase clinically relevant cytokine environmental intervention immunoregulation inner city novel primary outcome programs remediation secondary outcome stem treatment duration

项目摘要

DESCRIPTION (provided by applicant): The recommendation for environmental control measures as key components in the management of asthma stems in part from previous research that found exposure to mouse allergen may contribute greatly to the burden of inner-city asthma, especially in the Northeast. This group has shown that mouse-targeted integrated pest management (IPM) successfully reduces residential mouse allergen levels by greater than 75%. Evidence also suggests that reduction of allergens may result in immune modulation that could influence favorably the future course of disease. This application focuses on determining such molecular mechanisms. This project will collaborate with an NIAID funded randomized, controlled trial to assess the efficacy of IPM in children with moderate to severe asthma who live in homes with high levels of mouse allergen (1U01AI083238). Epigenetic alterations in genes associated with asthma are believed to occur following exposure to environmental toxicants, including allergens. We propose to determine whether remediation of mouse allergen is associated with changes in epigenetic marks and expression of genes important to the regulation of allergic airway disease, and whether these are associated with improvement in asthma. We will investigate multiple key steps in this pathway by collecting and analyzing measures of 1) allergen levels, 2) buccal DNA methylation levels of asthma regulatory genes under epigenetic control: interferon (IFN)¿ and Forkhead box P3 (Foxp3), 3) levels of gene expression, and 4) asthma symptoms prior to and following mouse allergen-targeted IPM or control intervention. We hypothesize that 1) Reduction in indoor mouse allergen levels will be associated with changes in buccal cell DNA methylation of asthma counter-regulatory genes important to Th cytokine production (IFN¿) and T cell regulation (Foxp3), 2) Changes in DNA methylation of asthma genes will be associated with a reduction in asthma symptoms after completion of a mouse allergen intervention among n=200 moderate to severe asthmatic children. If the aims are achieved, we will develop research that helps define a 'molecular footprint' of mouse allergen exposure and its remediation on DNA methylation. This new direction may result in novel biomarkers that could inform us about the efficacy of interventions against environmental toxicants important to asthma, and its immune modulation, addressing a critical clinical and public health problem. Home visits will be conducted every 3 months to assess settled dust mouse allergen levels and other evidence of infestation. Symptom data will be collected every 3 months either during clinic visits or telephone calls. Buccal specimens will be collected at screening, 6 months (following IPM at 0.5, 1.5 months, and if necessary 3 months) and 12 months. Analyses will control for the appropriate covariates. This proposed study would be the first to study environmental epigenetic regulation in the context of a randomized environmental intervention. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page PUBLIC HEALTH RELEVANCE: The recommendation for environmental control measures as key components in the management of asthma stems in part from previous research that found exposure to mouse allergen may contribute greatly to the burden of inner-city asthma, especially in the Northeast. This group has shown that mouse-targeted integrated pest management successfully reduces residential mouse allergen levels by greater than 75%. We now propose to determine whether remediation of mouse allergen is associated with changes in epigenetic marks and expression of genes important to the regulation of allergic airway disease, and whether these in turn are associated with fewer asthma symptoms. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

描述（由申请人提供）：将环境控制措施作为哮喘管理关键组成部分的建议部分源于先前的研究，该研究发现接触小鼠过敏原可能会极大地加重市中心哮喘的负担，尤其是在东北部。该小组表明，针对小鼠的综合害虫管理 (IPM) 成功地将居住的小鼠过敏原水平降低了 75% 以上。证据还表明，过敏原的减少可能会导致免疫调节，从而对未来的疾病进程产生有利的影响。该应用的重点是确定此类分子机制。该项目将与 NIAID 资助的随机对照试验合作，评估 IPM 对生活在小鼠过敏原水平较高的家庭中的中度至重度哮喘儿童的疗效 (1U01AI083238)。与哮喘相关的基因中的变化被认为是在暴露于环境毒物（包括过敏原）后发生的，我们建议确定小鼠过敏原的修复是否与表观遗传标记和调节重要基因表达的变化有关。我们将通过收集和分析 1) 过敏原水平、2) 表观遗传控制下哮喘调节基因的口腔 DNA 甲基化水平来研究该途径中的多个关键步骤：干扰素。 (干扰素)¿和 Forkhead box P3 (Foxp3)，3) 基因表达水平，以及 4) 在针对小鼠过敏原的 IPM 或对照干预之前和之后的哮喘症状，我们发现 1) 室内小鼠过敏原水平的降低将与变化相关。口腔细胞中哮喘反调节基因的 DNA 甲基化对 Th 细胞因子产生 (IFN¿) 和 T 细胞调节 (Foxp3) 很重要，2) 哮喘基因 DNA 甲基化的变化将是在 n = 200 名中度至重度哮喘儿童中完成小鼠过敏原干预后，与哮喘症状的减少相关。如果目标实现，我们将开展研究，帮助确定小鼠过敏原暴露的“分子足迹”及其补救措施。 DNA 甲基化这一新方向可能会产生新的生物标志物，这些标志物可以让我们了解针对哮喘及其免疫调节的重要环境毒物的干预措施的有效性，从而解决关键的临床和公共卫生问题。评估每 3 个月收集一次尘鼠过敏原水平和其他感染症状数据，并在筛查时收集口腔样本，第 6 个月（IPM 后第 0.5 个月、第 1.5 个月，如有必要，第 3 个月）。月）和 12 个月。这项拟议的研究将是第一个在随机环境干预背景下研究环境表观遗传调控的研究。 398/2590 (Rev. 06/09) 页面延续格式页面公共卫生相关性：将环境控制措施作为哮喘管理关键组成部分的建议部分源于先前的研究，该研究发现接触小鼠过敏原可能会极大地加重城市内哮喘的负担，尤其是在东北部地区。研究表明，针对小鼠的综合害虫管理成功地将居住小鼠过敏原水平降低了 75% 以上，我们现在建议确定小鼠过敏原的修复是否与表观遗传标记和对过敏调节重要的基因表达的变化有关。气道疾病，以及这些疾病是否与较少的哮喘症状相关 PHS 398/2590（修订版 06/09）页继续格式页。