Obesity and Childhood Asthma: The Role of Adipose Tissue

肥胖和儿童哮喘：脂肪组织的作用

基本信息

批准号：
10378481
负责人：
Erick Forno
金额：
$ 61.41万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10378481
关键词：
Abbreviations Acute Adipose tissue Affect Anthropometry Asthma Biological Markers Blood Body Composition Body fat Body mass index Candidate Disease Gene Cardiovascular Diseases Cells Child Childhood Asthma DNA Methylation Data Development Diabetes Mellitus Disease Elderly Epigenetic Process Epithelial Epithelial Cells Functional disorder Gene Expression Gene Expression Alteration Genes Genotype Goals Heritability Immune Inflammatory Insulin Resistance Intra-abdominal Lead Literature Measures Mediator of activation protein Morbid Obesity Morbidity - disease rate Obesity Outcome Overweight Pathogenesis Pathway interactions Patients Persons Pharmaceutical Preparations Pharmacology Phenotype Process Production Public Health Quality of life Regulation Research Role Sample Size Severities Severity of illness Signal Transduction Smooth Muscle Myocytes Source Testing Tissue-Specific Gene Expression Tissues Transcript Validation Vulnerable Populations adipokines asthma exacerbation asthmatic atopy bronchial epithelium cohort cost cytokine disorder control electric impedance epigenetic regulation epigenome-wide association studies epigenomics genetic variant genome-wide high risk improved indexing innovation insight new therapeutic target novel novel strategies obesity in children obesity management obesity-associated asthma overweight child pulmonary function recruit respiratory smooth muscle response secondary outcome subcutaneous therapeutic target transcriptome transcriptome sequencing transcriptomics treatment response

项目摘要

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.

项目摘要童年哮喘和肥胖都是主要的公共卫生问题。有很大的证据表明在两种疾病之间；肥胖儿童哮喘的严重程度增加，控制不佳和减少用药反应。然而，迄今为止，基础机制尚不清楚。我们的中心假设是肥胖的哮喘是由表观遗传调节和转录组中的变化驱动的脂肪组织。为了检验这一假设，我们将招募一群患有哮喘，肥胖，或对照的儿童我们将在其中进行广泛的表型，并获得皮下和腹腔内脂肪组织。除BMI外，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。在特定目标1中，我们将评估脂肪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）与肥胖和哮喘相关该队列在调整了相关的协变量后。次要措施将包括身体成分和肥胖分布，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，DNA甲基化和RNA-SEQ数据。在特定目标2中，我们将使用评估肥胖和哮喘儿童哮喘严重程度和控制的测量方法相同的方法。我们将专注于急性加重，哮喘控制测试（ACT）分数和肺功能变化。并具体 AIM 3，我们将通过评估正常的差异基因表达来进行初始功能/因果验证以及哮喘的支气管上皮和气道平滑肌细胞，以响应于 AIMS 1-2中鉴定出的最高基因以及文献中肥胖哮喘的其他候选基因。这提案通过关注肥胖哮喘的“来源”组织来创新，而不是使用血液生物标志物或通过验证顶部结果对“靶”组织的影响。阐明脂肪组织与肥胖哮喘相关的途径将对我们对这种表型的理解产生关键影响并可能使我们能够确定改善这些患者管理的方法。