Epigenetics of severe asthma

严重哮喘的表观遗传学

基本信息

批准号：
9916817
负责人：
Syed HASAN Arshad
金额：
$ 76.9万
依托单位：
LA JOLLA INSTITUTE FOR IMMUNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-23 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9916817
关键词：
Adrenal Cortex Hormones Adult Affect American Asthma Automobile Driving Bioinformatics Biological Assay Blood Blood Cells Blood specimen Cells ChIP-seq Chromatin Chromatin Conformation Capture and Sequencing Clinical Collaborations DNA DNA Modification Process Data Set Development Disease Drug Targeting Enhancers Epigenetic Process Event Failure Funding Gene Expression Profiling Genes Genetic Fingerprintings Genetic Transcription Genome Health Histones Human Immune Immune response Immunology procedure Inhalation Institutes Lead Letters Libraries Link Location Lysine MHC binding peptide Malignant Neoplasms Maps Measures Messenger RNA Methods Modification Molecular Nucleic Acid Regulatory Sequences Oral Pathogenesis Pathogenicity Pathway interactions Patients Pharmaceutical Preparations Phenotype Physicians Population Process Publishing RNA Recruitment Activity Regulatory Element Research Research Personnel Risk Role Severities Signal Transduction Small Interfering RNA T memory cell T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets Testing Th2 Cells Time Transcript United States National Institutes of Health asthmatic asthmatic patient base cell type cellular development chromatin immunoprecipitation clinical phenotype cohort comparative drug development epigenetic marker epigenomics follow-up gene function genetic variant genome wide association study genome-wide histone modification human disease immune function knock-down molecular marker monocyte new therapeutic target next generation sequencing novel novel strategies novel therapeutics novel vaccines prevent programs promoter small hairpin RNA tool transcriptome sequencing

项目摘要

PROJECT SUMMARY In this multi-PI proposal we will investigate the role of epigenetic mechanisms in driving severe asthma pathogenesis. The identification of molecular players/pathways that lead to pathogenic immune responses in asthma will be beneficial for the discovery of drug targets and development of new vaccine strategies to prevent asthma. Genome-wide enhancer profiling is a powerful new tool that has allowed investigators to precisely track genes and their cognate enhancers and thus capture molecular events involved in cellular development and differentiation. We have successfully micro-scaled this tool to enable large-scale human studies that have the potential to unravel novel molecular mechanisms underlying human diseases. In this proposal, we will define asthma-related epigenetic markers in ~100 patients with severe asthma, and correlate these with clinical phenotypes to obtain specific molecular markers for distinguishable disease states (i.e. severe asthma phenotypes). We will capitalize on three longitudinal asthma cohorts: (i) the Wessex AsThma CoHort of difficult asthma (WATCH), an observational clinical cohort with on-going active recruitment (~25 new cases/month) that currently consists of ~250 subjects with severe asthma, who are actively followed up by the treating physicians (PI Ramesh/Hasan, UK), (ii) The NIH-funded IOW, UK cohort of >100 well-phenotyped mild asthmatics; (iii) the La Jolla Institute (LJI) cohort of 40 subjects with mild-to-moderate asthma, who have provided blood samples every 6 months over two years. In Aim 1, we will profile the enhancer landscape in immune cell types relevant to severe asthma pathogenesis (naïve, TH2 memory T cell subsets and classical monocytes), isolated from longitudinally collected blood samples from 200 subjects with varying asthma severity. We will perform comparative bioinformatics analysis to identify the immune cell enhancers linked to severe asthma. We will also perform transcriptional profiling of blood and airway immune cells to precisely define the genes that are affected (influenced) by the enhancers identified in severe asthma. In Aim 2, we will define the target genes of severe asthma associated enhancers and determine if genetics variants linked to asthma risk affect their function. We will then test the function of these genes in primary human T cells using optimized micro-scaled immunological assays. Overall, our discovery-based epigenetic studies and follow up functional studies will identify novel genes and pathways involved in severe asthma and corticosteroid insensitivity, and could open novel ways to treat severe asthma.

项目摘要在此多PI提案中，我们将研究表观遗传机制在驱动严重哮喘中的作用发病。鉴定分子玩家/途径，导致致病性免疫反应哮喘将有益于发现药物靶标和开发新的疫苗策略预防哮喘。全基因组增强子分析是一种强大的新工具，使研究人员得以实现精确跟踪基因及其同源增强子，从而捕获与细胞有关的分子事件发展与分化。我们已经成功地对此工具进行了微尺度，以实现大规模的人类有可能揭示人类疾病潜在的新分子机制的研究。在这个提案，我们将在约100例严重哮喘患者中定义与哮喘相关的表观遗传标记，并相关这些具有临床表型，以获得可区分疾病态的特定分子标记（即严重的哮喘表型）。我们将利用三个纵向哮喘同龄人：（i）Wessex哮喘困难哮喘（观察）的队列，这是一种持续有效招募的观察性临床队列（〜25新的案件/月）目前由约250名患有严重哮喘的受试者组成，他们会积极跟踪治疗医师（Pi Ramesh/Hasan，UK），（ii）NIH资助的英国同类，> 100型良好的轻度哮喘患者；（iii）有40名受试者的La Jola Institute（LJI），患有轻度至中度哮喘，在两年内每6个月提供一次血液样本。在AIM 1中，我们将介绍与严重哮喘发病机理有关的免疫细胞类型中的增强剂景观（幼稚，Th2记忆T细胞子集和经典单核细胞），从纵向收集的血液中分离出来来自200名受试者哮喘严重程度不同的样本。我们将执行比较生物信息学分析确定与严重哮喘相关的免疫细胞增强剂。我们还将执行转录分析血液和气道免疫细胞精确定义受增强剂影响（影响）的基因在严重的哮喘中确定。在AIM 2中，我们将定义严重哮喘相关增强剂的靶基因并确定与哮喘风险相关的遗传学变异是否会影响其功能。然后，我们将测试这些基因在原代人T细胞中使用优化的微型免疫学测定。总体而言，我们的基于发现的表观遗传研究和后续功能研究将识别新的基因和途径涉及严重的哮喘和皮质类固醇不敏，可以打开治疗严重哮喘的新方法。