Asthma: An Epidemic Caused by Epigenetics?

哮喘：表观遗传学引起的流行病？

• 批准号: 7727660
• 负责人: GREGORY P COSGROVE
• 金额: $ 67.16万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7727660
• 关键词: Accounting; Address; Adult; Affect; Asthma; Biological; Child; Complex; DNA Methylation; Data; Derivation procedure; Developed Countries; Developing Countries; Development; Dietary Supplementation; Disease; Environment; Environmental Exposure; Epidemic; Epigenetic Process; Etiology; Genes; Genetic; Genetic Predisposition to Disease; Goals; Human; Immune; Incidence; Individual; Inheritance Patterns; Investments; Knowledge; Lead; Link; Lung; Mature T-Lymphocyte; Measures; Methylation; Mus; Parents; Pathogenesis; Patients; Pattern; Perinatal Exposure; Peripheral Blood Mononuclear Cell; Phenotype; Play; Population; Population Study; Prevalence; Public Health; Research; Risk; Role; Sampling; Severities; Siblings; Stress; Testing; Validation; airway epithelium; allergic airway disease; base; case control; disorder prevention; falls; genetic variant; imprint; in utero; novel strategies; public health relevance; transcription factor

DESCRIPTION (provided by applicant): The challenge that we intend to address in this proposal is the extent to which epigenetic mechanisms contribute to the etiology of asthma in humans. Several lines of evidence support a role for epigenetics in asthma. Asthma, like epigenetic mechanisms, has a non-Mendelian and parent-of-origin pattern of inheritance, is influenced by the environment, and is modified by in utero exposures. Furthermore, the transcription factors that are involved in the development of mature T cells (Th1, Th2, and Tregs), that are critical to the Th2 immune phenotype in asthma, are regulated by epigenetic mechanisms. Although the difference in asthma incidence in developed versus developing countries has previously been attributed to infectious exposures, the mechanisms accounting for these differences have never been fully explained. We have recently demonstrated that in utero dietary supplementation with methyl donors regulates locus-specific DNA methylation and predisposes mice to allergic airway disease by skewing towards a Th2 phenotype. Based on these observations, we hypothesize that epigenetic mechanisms play a fundamental role in the etiology of asthma by modulating the methylation state and transcriptional activity of critical genes that affect immune maturation and lead to the development of asthma. In the proposed project, we intend to use a novel approach to determine the extent to which epigenetic mechanisms contribute to the etiology of asthma in humans (see Figure). We will measure global methylation patterns in a panel of human sibling pairs discordant for asthma (Aim 1), and in airway epithelia and peripheral blood mononuclear cells (PBMCs) obtained from patients with asthma and controls (Aim 2). We will combine these global methylation marks with our knowledge of global methylation patterns in mouse lungs with allergic airway disease, and then confirm these methylation patterns with direct sequencing (Aim 3). We then propose to validate and further characterize these findings in two independent study populations. Using the original discordant sibling pair sample and their parents, we will test whether these targets are imprinted (Aim 4). Using a large, independent sample of asthmatic cases and controls for which extensive environmental and genetic data are available, we will test whether these targets replicate and whether they are influenced by either environmental or genetic factors (Aim 5). Identifying unique epigenetic marks and linking them to other etiologic factors, such as environmental exposures and genetic variants, will transform our understanding of the etiology and pathogenesis of asthma, and lead to more effective approaches to disease prevention and treatment. Derivation Confirmation Validation Aim 1: Discordant Sibling Pairs Aim 2: Airway Epithelia and PBMCs Murine Lung DNA Methylation Aim 3: Confirm Epigenetic Targets Aim 4: Imprinting Aim 5: Case Control PUBLIC HEALTH RELEVANCE: Asthma is a complex, heritable disease affecting more than 11.2% of the U.S. population; ~9 million children and ~23 million adults. Despite major investments that have been made in asthma research over the past two decades, the disease remains a major public health problem that paradoxically is increasing in prevalence, incidence, and severity. At present, both environmental exposures and genetic variants fall far short in explaining the etiology of asthma. Moreover, although many environmental and genetic factors place individuals at increased risk of developing disease, we currently lack a biological explanation for how these etiological factors interact. While epigenetic mechanisms appear to serve as a critical biological switch between genetic vulnerability and environmental stress, these mechanisms have not yet been studied in humans with asthma. The overarching goal of this proposal is the extent to which epigenetic mechanisms contribute to the etiology of asthma in humans. We believe a better understanding of the etiology and pathogenesis of asthma will transform our conceptual understanding of this disease, and lead to more effective strategies for disease prevention and treatment.

描述（由申请人提供）：我们打算在此提案中应对的挑战是表观遗传机制有助于人类哮喘的病因。几条证据支持表观遗传学在哮喘中的作用。像表观遗传机制一样，哮喘具有非孟德尔和父母的遗传模式，受环境的影响，并在子宫暴露中被修饰。此外，成熟T细胞（Th1，Th2和Tregs）与Th2免疫表型至关重要的成熟T细胞（Th1，Th2和Treg）所涉及的转录因子受到表观遗传机制的调节。尽管发达国家与发展中国家哮喘发病率的差异以前归因于传染性暴露，但涉及这些差异的机制从未得到充分解释。我们最近证明，在子宫内饮食中补充甲基供体可以调节基因座特异性的DNA甲基化，并使小鼠偏向于Th2表型，使小鼠对过敏气道疾病。基于这些观察结果，我们假设表观遗传机制通过调节影响免疫成熟并导致哮喘发展的关键基因的甲基化状态和关键基因的转录活性，在哮喘的病因中起着基本作用。在拟议的项目中，我们打算使用一种新颖的方法来确定表观遗传机制在多大程度上促进人类哮喘的病因（见图）。我们将在人类兄弟姐妹对中的全球甲基化模式不一致（AIM 1），在气道上皮和外周血单核细胞（PBMC）中，从患有哮喘和对照患者获得（AIM 2）中（AIM 2）。我们将将这些全球甲基化标记与我们对具有过敏性气道疾病的小鼠肺中全球甲基化模式的了解相结合，然后通过直接测序确认这些甲基化模式（AIM 3）。然后，我们建议在两个独立的研究人群中验证和进一步表征这些发现。使用原始的不和谐兄弟姐妹对样本及其父母，我们将测试这些目标是否印记（AIM 4）。使用可用的广泛环境和遗传数据的大量独立的哮喘病例和对照样本，我们将测试这些目标是否复制，以及它们是否受环境或遗传因素的影响（AIM 5）。识别独特的表观遗传标记并将其与其他病因学因素（例如环境暴露和遗传变异）联系起来，将改变我们对哮喘的病因学和发病机理的理解，并导致更有效的预防疾病和治疗方法。推导确认验证目标1：不一致的同胞对目标2：气道上皮和PBMCS鼠肺肺DNA甲基化目标3：确认表观遗传目标目标4：烙印目标5：案例控制公共卫生相关性：哮喘是一种复杂的，可比美国人群占11.2％的复杂疾病；约900万儿童和约2300万成人。尽管过去二十年来对哮喘研究进行了重大投资，但这种疾病仍然是一个主要的公共卫生问题，矛盾的是，患病率，发病率和严重程度正在增加。目前，环境暴露和遗传变异在解释哮喘的病因方面都差不多。此外，尽管许多环境和遗传因素使个体患疾病的风险增加，但我们目前缺乏对这些病因因素如何相互作用的生物学解释。尽管表观遗传机制似乎是遗传脆弱性和环境压力之间的关键生物学转换，但在患有哮喘的人类中，这些机制尚未研究。该提议的总体目标是表观遗传机制在人类哮喘的病因中有助于多大程度。我们认为，对哮喘的病因和发病机理的更好理解将改变我们对这种疾病的概念理解，并为预防疾病和治疗提供更有效的策略。