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：
10813753
负责人：
Erick Forno
金额：
$ 49.09万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-11-22 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10813753
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 Cells Epithelium Functional disorder Gene Expression Gene Expression Alteration Genes Genotype Goals Heritability Immune Inflammatory Insulin Resistance Intra-abdominal Literature Measures Mediator Morbid Obesity Morbidity - disease rate Obesity Outcome Overweight Pathogenesis Pathway interactions Patients Persons Pharmaceutical Preparations Phenotype Process Production Proliferating 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 pharmacologic 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.

项目概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者之间存在关联。两种疾病之间；患有哮喘的肥胖儿童的哮喘严重程度增加，控制不佳，并且哮喘减少然而，迄今为止，我们的中心假设还不清楚。肥胖哮喘是由表观遗传调控和转录组活性的变化驱动的为了检验这一假设，我们将招募一组患有哮喘、肥胖症或两者兼有的儿童或对照组，我们将对其进行广泛的表型分析，并获得皮下和腹腔内的脂肪组织。除了BMI之外，我们还会评估通过人体测量测量的其他肥胖指数和身体成分在具体目标 1 中，我们将评估脂肪的转录组和表观遗传变化。与肥胖和哮喘相关的组织（分别使用 RNA-seq 和全基因组 DNA 甲基化）在调整相关协变量后，该队列的次要指标将包括身体成分和然后我们将整合肥胖分布、特应性和炎症生物标志物，在特定目标 2 中，我们将使用 mQTL、eQTL 和 eQTM 分析的 DNA 甲基化和 RNA-seq 数据。使用相同的方法来评估肥胖和哮喘儿童的哮喘严重程度和控制情况。将重点关注急性加重、哮喘控制测试 (ACT) 评分和肺功能变化。目标 3，我们将通过评估正常人中的差异基因表达来进行初步功能/因果验证和哮喘支气管上皮细胞和气道平滑肌细胞，对产品治疗作出反应目标 1-2 中确定的主要基因，以及文献中肥胖哮喘的其他候选基因。该提案通过关注肥胖哮喘的“源”组织进行创新，而不是使用血液生物标志物或介质，并验证最佳结果对“目标”组织的影响。与肥胖哮喘相关的途径将对我们理解这种表型产生重要影响并可能使我们能够找到改善这些患者管理的方法。