Mouse allergen intervention and DNA methylation of asthma regulatory genes

描述（由申请人提供）：将环境控制措施作为哮喘管理的关键组成部分的建议部分源于先前的研究，该研究发现暴露于小鼠过敏原可能会极大地增加内城哮喘的负担，特别是在东北部。该小组已经表明，针对小鼠的综合害虫管理（IPM）成功地将住宅小鼠过敏原水平降低了75%以上。证据还表明，减少过敏原可能会导致免疫调节，从而对疾病的未来进程产生有利影响。本申请的重点是确定这样的分子机制。该项目将与NIAID资助的随机对照试验合作，以评估IPM对生活在高水平小鼠过敏原家庭中的中度至重度哮喘儿童的疗效（1U 01 AI 083238）。与哮喘相关的基因的表观遗传改变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补救是否与表观遗传标记和对过敏性气道疾病的调节重要的基因表达的变化相关，以及这些是否与哮喘的改善相关。我们将通过收集和分析以下指标来研究该途径中的多个关键步骤：1）过敏原水平，2）表观遗传控制下哮喘调节基因的颊DNA甲基化水平：干扰素（IFN）和叉头盒P3（Foxp 3），3）基因表达水平，以及4）小鼠过敏原靶向IPM或对照干预前后的哮喘症状。我们假设：1）室内小鼠过敏原水平的降低与口腔细胞DNA甲基化的变化有关，口腔细胞DNA甲基化的变化对Th细胞因子（IFN？）和T细胞调节（Foxp 3），2）哮喘基因的DNA甲基化的变化将与小鼠变应原干预完成后哮喘症状的减轻相关，其中n= 10。200名中度至重度哮喘儿童。如果目标实现，我们将开展研究，帮助定义小鼠过敏原暴露的“分子足迹”及其对DNA甲基化的补救。这一新的方向可能会产生新的生物标志物，可以告诉我们对哮喘重要的环境毒物的干预效果，及其免疫调节，解决关键的临床和公共卫生问题。 将每3个月进行一次家访，以评估沉降尘小鼠过敏原水平和其他感染证据。将每3个月在门诊访视或电话访视期间收集症状数据。将在筛选、6个月（IPM后0.5、1.5个月，如有必要，3个月）和12个月时采集颊部样本。分析将控制适当的协变量。这项拟议的研究将是第一个在随机环境干预的背景下研究环境表观遗传调控的研究。PHS 398/2590（Rev.06/09）

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