Obesity and Childhood Asthma: The Role of Adipose Tissue

项目摘要 儿童哮喘和肥胖都是主要的公共卫生问题。有强有力的证据表明 两种疾病之间;患有哮喘的肥胖儿童哮喘严重程度增加，控制不良， 药物反应。然而，到目前为止，人们对基本机制还没有很好的理解。我们的核心假设 肥胖性哮喘是由表观遗传调节和转录组活动的变化驱动的， 脂肪组织为了验证这一假设，我们将招募一组患有哮喘、肥胖或两者兼而有之的儿童， 我们将在其中进行广泛的表型分析，并获得皮下和腹内脂肪组织。 除了BMI，我们还将评估通过人体测量法测量的肥胖和身体成分的其他指标 和阻抗分析。在具体目标1中，我们将评估脂肪组织中的转录组和表观遗传变化， 组织（分别使用RNA-seq和全基因组DNA甲基化）与肥胖和哮喘相关， 调整相关协变量后，该队列。次要措施将包括身体成分， 肥胖分布以及特应性和炎症生物标志物。然后我们将整合全基因组基因分型， 通过mQTL、eQTL和eQTM分析的DNA甲基化和RNA-seq数据。在具体目标2中，我们将使用 同样的方法来评估肥胖和哮喘儿童的哮喘严重程度和控制措施。我们 将重点关注急性加重、哮喘控制测试（ACT）评分和肺功能变化。和特定 目的3，我们将通过评估正常人中的差异基因表达来进行初步的功能/因果验证。 以及哮喘性支气管上皮细胞和气道平滑肌细胞，对用以下产品治疗的响应 目的1-2中鉴定的最高基因，以及来自文献的肥胖性哮喘的其它候选基因。这 这项提案的创新之处在于关注肥胖性哮喘的“源”组织，而不是使用血液生物标志物或 介质，并通过验证对“靶”组织的最佳结果的影响。阐明脂肪组织 与肥胖性哮喘相关的通路将对我们理解这种表型具有重要意义 并可能使我们能够确定改善这些患者管理的方法。

PROJECT SUMMARY Both childhood asthma and obesity are major public health problems. There is strong evidence of an association between both diseases; obese children with asthma have increased asthma severity, poor control, and reduced medication response. Yet, to date, the underpinning mechanisms are not well understood. Our central hypothesis is that the obese asthma is driven by changes in the epigenetic regulation and transcriptomic activity within adipose tissue. To test this hypothesis, we will recruit a cohort of children with asthma, obesity, both, or controls, in whom we will perform extensive phenotyping, and obtain subcutaneous and intra-abdominal adipose tissue. In addition to BMI, we will assess other indices of adiposity and body composition measured by anthropometry and impedance analysis. In Specific Aim 1, we will assess the transcriptomic and epigenetic changes in adipose tissue (using RNA-seq and genome-wide DNA methylation, respectively) associated with obesity and asthma in this cohort, after adjustment for relevant covariates. Secondary measures will include body composition and adiposity distribution, and atopy and inflammatory biomarkers. We will then integrate genome-wide genotyping, DNA methylation, and RNA-seq data via mQTL, eQTL, and eQTM analyses. In Specific Aim 2, we will use the same approach to evaluate measures of asthma severity and control in children with obesity and asthma. We will focus on acute exacerbations, Asthma Control Test (ACT) scores, and lung function changes. And in Specific Aim 3, we will conduct an initial functional/causal validation by assessing differential gene expression in normal and asthmatic bronchial epithelial and airway smooth muscle cells, in response to treatment with the products of the top genes identified in Aims 1-2, as well as other candidate genes for obese asthma from the literature. This proposal innovates by focusing on the “source” tissue of obese asthma, rather than using blood biomarkers or mediators, and by validating the effect of the top results on the “target” tissues. Elucidating adipose tissue pathways associated with obese asthma will have critical implications for our understanding of this phenotype and may allow us to identify ways to improve the management of these patients.