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（通过应用程序提供）：环境控制措施作为哮喘植物管理中的关键组成部分的建议部分是从先前的研究中发现暴露于小鼠过敏原的研究，可能会对内城哮喘的伯恩伯恩（Burnen）产生巨大贡献，尤其是在东北部。该小组表明，以小鼠为目标的综合害虫管理（IPM）成功地将住宅小鼠过敏原水平降低了75％。证据还表明，过敏原的降低可能会导致免疫调节，从而可能影响未来的疾病过程。该应用重点是确定这种分子机制。该项目将与一项NIAID资助的随机，对照试验合作，以评估居住在具有高水平小鼠过敏原（1U01AI083238）的家庭中的中度至重度哮喘儿童中IPM的效率。相信，与哮喘相关的基因的表观遗传改变我们将通过收集和分析该途径中的多个关键步骤，通过收集和分析1）过敏原水平的度量，2）表观遗传控制下的哮喘调节基因的颊DNA甲基化水平：Interferon（Interferon（Interferon）（Interferon（Interferon）（Interferon）（Interferon（Infferon（IFN）））（IFN）�和Forkhead Box P3（Fox P3），3），以及3），以及3），3）及4次，4），以及4），4），以及4），4）和4），4）severs of Gen e e empl of Gentma astman和4）靶向过敏原的IPM或控制干预措施。我们假设1）室内小鼠过敏原水平降低将与哮喘反调节基因的颊细胞DNA甲基化的变化有关，对细胞因子的产生（IFN¿）和T细胞调节（FOXP3），2），2）哮喘基因的DNA甲基化的变化与哮喘基因的DNA甲基化的变化相关，使哮喘基因的DNA甲基化的变化与ASTMA的DNA甲基化的变化相关。哮喘儿童。如果实现目标，我们将开发研究，有助于定义小鼠过敏原暴露的“分子足迹”及其对DNA甲基化的修复。这个新的方向可能会导致新颖的生物标志物，可以告知我们针对环境有毒物质对哮喘重要的干预效率及其免疫调节，从而解决了关键的临床和公共卫生问题。每3个月将进行一次访问，以评估定居的尘埃鼠标过敏原水平和其他侵扰证据。症状数据将在诊所就诊或电话期间每3个月收集一次。将在筛查时，6个月（在0.5、1.5个月以及必要的（如果需要3个月）和12个月的情况下，将收集颊标本。分析将控制适当的协变量。这项拟议的研究将是在随机环境干预的背景下第一个研究环境表观遗传调节的研究。 PHS 398/2590（修订版06/09）页面延续格式页面公共卫生相关性：环境控制措施作为哮喘植物管理中的关键组成部分的建议部分是从先前的研究中发现暴露于小鼠过敏原的，可能会极大地促进内城哮喘的燃烧，尤其是在东北。该小组表明，以小鼠为目标的综合害虫管理成功地将居民小鼠过敏原水平降低了75％。现在，我们建议确定小鼠过敏原的修复是否与表观遗传标记的变化和对调节过敏性气道疾病重要的基因表达有关，以及这些基因是否与较少的哮喘症状有关。 PHS 398/2590（修订版06/09）页面延续格式页面