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

• 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
• 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

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的关键组成部分的建议部分源于之前的研究，该研究发现，暴露于老鼠变应原可能会极大地增加市中心哮喘的负担，特别是在东北部。该小组已经表明，以老鼠为目标的综合虫害管理(IPM)成功地将住宅老鼠的过敏原水平降低了75%以上。证据还表明，过敏原的减少可能会导致免疫调节，这可能会对未来的病程产生有利影响。这项应用的重点是确定这种分子机制。该项目将与NIAID资助的一项随机对照试验合作，评估IPM对居住在老鼠变应原水平较高的家庭(1U01AI083238)的中到重度哮喘儿童的疗效。与哮喘相关的基因的表观遗传变化被认为是在暴露于包括过敏原在内的环境毒物之后发生的。我们建议确定小鼠变应原的修复是否与表观遗传标志的变化和对调节过敏性呼吸道疾病重要的基因的表达有关，以及这些变化是否与哮喘的改善有关。我们将通过收集和分析以下指标来研究这一途径的多个关键步骤：1)变应原水平，2)表观遗传控制下哮喘调节基因的口腔DNA甲基化水平：干扰素和Forkhead box P3(Foxp3)，3)基因表达水平，以及4)哮喘症状在小鼠变应原靶向IPM或对照干预前后的水平。我们假设：1)室内小鼠变应原水平的降低将与哮喘逆调控基因口腔细胞DNA甲基化的变化有关，这些基因对Th细胞因子的产生(干扰素)和T细胞调节(Foxp3)至关重要；2)在n=200名中到重度哮喘儿童中，哮喘基因DNA甲基化的变化将与完成小鼠变应原干预后哮喘症状的减轻有关。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’及其对DNA甲基化的补救。这一新的方向可能导致新的生物标志物的产生，这些生物标志物可以告诉我们针对对哮喘重要的环境毒物的干预的有效性，以及它的免疫调节，解决一个关键的临床和公共卫生问题。将每3个月进行一次家访，以评估已确定的灰尘、老鼠过敏原水平和其他感染证据。症状数据将每3个月在诊所就诊或电话中收集一次。口腔样本将在筛查时、6个月(IPM后0.5个月、1.5个月和必要时3个月)和12个月收集。分析将控制适当的协变量。这项拟议的研究将是第一次在随机环境干预的背景下研究环境表观遗传调控。PHS 398/2590(06/09版)页面续格式页面 公共卫生相关性：将环境控制措施作为哮喘管理的关键组成部分的建议部分源于之前的研究，该研究发现，暴露于老鼠变应原可能会极大地增加市中心哮喘的负担，特别是在东北部。该小组已经表明，以老鼠为目标的综合害虫管理成功地将住宅老鼠的过敏原水平降低了75%以上。我们现在建议确定小鼠变应原的修复是否与表观遗传标志和对调节过敏性呼吸道疾病重要的基因表达的变化有关，以及这些变化是否反过来与较少的哮喘症状有关。PHS 398/2590(06/09版)页面续格式页面