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Genetic and Epigenetic Determinants of Pediatric Obesity-Associated Asthma

儿童肥胖相关哮喘的遗传和表观遗传决定因素

基本信息

批准号：
10092412
负责人：
Deepa Rastogi
金额：
$ 2.16万
依托单位：
CHILDREN'S RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10092412
关键词：
Genetic Epigenetic Determinants Pediatric Obesity

项目摘要

Obesity-associated asthma is a distinct entity characterized by worse airflow obstruction and suboptimal response to conventional asthma management that disproportionately affects urban children. However, its pathogenesis is poorly understood. In contrast to atopic T helper (Th) type 2 inflammation found in “classic” childhood asthma, studies from our lab indicate that obesity-associated asthma is associated with non-atopic Th1 inflammation that correlates with lower airway obstruction. Additionally, we found decreased promoter methylation of genes associated with T cell signaling suggesting that epigenetic mechanisms may mediate the distinct asthma phenotype in obese children. However, molecular mechanisms that underlie non-atopic inflammation in obese asthmatics are not known. Asthma and obesity are multifactorial diseases, determined by genetic susceptibility, including that related to ancestry, epigenetic modification by environmental exposures, and non-genetic environmental factors that influence gene expression and thus clinical phenotype. Hence, investigation of the association between gene expression, genetic polymorphisms, and epigenetic modulation may identify a unifying molecular mechanism to explain the obese asthma phenotype observed in urban children. We have collected 200 samples from children in the Bronx during the past 5 years of this award to test the hypothesis that Th-cell gene expression in obese asthmatics differs from that in normal-weight asthmatics, is determined by genetic polymorphisms (eQTLs and ancestry-specific haplotypes), and is influenced by DNA methylation. We proposed the following specific aims to address these hypotheses: (1) To quantify Th-cell gene expression differences between obese asthmatic and normal-weight asthmatic children. (2) To determine if epigenetic mechanisms mediate the effect of obesity on asthma. (3) To investigate if genetic polymorphisms, including ancestry-specific haplotypes, determine susceptibility to obesity-associated asthma. Th cells from 100 obese asthmatic and 100 normal-weight asthmatic children matched for age and gender have been isolated. We have simultaneously conducted genome-wide assays of a) gene expression by Directional Transcriptome Sequencing (RNA-seq) b) DNA methylation by HELP-tagging and c) genetic polymorphisms and single nucleotide polymorphisms (SNPs) informative of ancestry by array-based genotyping on these cells. Association of gene expression with genetic polymorphisms has identified variants predicting genetic susceptibility, which may be used to screen at-risk individuals. Verification studies of gene expression, DNA methylation, and genetic polymorphisms will now allow us to confirm the mechanistic molecular pathways specific to the obese asthma phenotype and improve our understanding of the disease pathogenesis. We will identify key molecules associated with non-atopic inflammation that could be novel targets for therapeutic intervention. Together, our study will provide fundamental insights into the pathogenesis of obesity-associated asthma among high-risk ethnicities. As a pediatric pulmonologist, my goal is to become an independent translational investigator in the field of pediatric asthma with a focus on the pulmonary effects of obesity. This K23 Mentored Patient Oriented- Research Career Development Award has allowed an in-depth study of genetic and epigenetic factors influencing Th cell mediated inflammation in obese asthmatic minority children. Findings from this proposal have provided the foundation for my R01 funding, which is focused on further investigation of the CDC42 pathway, identified as the top differentially expressed pathway in this K23 award. As our future goals, we plan to a) validate the key differentially expressed and/or methylated molecules in a separate cohort of children with poorly controlled disease b) confirm the role of key molecules in in-vitro cell culture systems with molecule- specific inhibitors and/or methylation modulators c) conduct a prospective investigation into links between obesity onset, rapidity of weight gain, development of asthma and Th cell differentiation, given the young age at which obesity-associated asthma afflicts urban children. The career development plan proposed in this application incorporated a) mentorship from established researchers in the field of epigenomics, obesity-related diseases, T cell biology, asthma, and mucosal and systemic immunity, b) coursework in genetics and epigenomics, and hand on training in novel methods to investigate gene expression, genotyping and DNA methylation, and c) participation and presentation at local, regional and national meetings. Together, the research proposed in this K23 award laid the foundation for my development into an independent investigator in the field of pediatric obesity-associated asthma. I am now focused on building on this foundation by verifying our findings to subsequently use these results as preliminary data for further investigation of the contribution of genetic susceptibility to childhood obesity- associated asthma.

肥胖相关性哮喘是一种独特的实体，其特征在于更严重的气流阻塞和次优的呼吸道阻塞。对传统哮喘管理的反应，不成比例地影响城市儿童。但其发病机制知之甚少。与“经典”中发现的特应性T辅助细胞（Th）2型炎症相反，儿童哮喘，我们实验室的研究表明，肥胖相关的哮喘与非特应性与下呼吸道阻塞相关的th 1炎症。此外，我们发现启动子与T细胞信号传导相关的基因甲基化，表明表观遗传机制可能介导了T细胞信号传导。肥胖儿童的哮喘表型。然而，非特应性的分子机制肥胖哮喘患者炎症尚不清楚。哮喘和肥胖是多因素疾病，由遗传易感性决定，包括相关的环境暴露引起的表观遗传修饰，以及非遗传环境因素，从而影响基因表达和临床表型。因此，研究基因之间的关联基因表达、遗传多态性和表观遗传调节可以确定一个统一的分子机制来解释在城市儿童中观察到的肥胖哮喘表型。我们收集了200个样本，儿童在布朗克斯在过去5年的这一奖项，以测试假设，Th细胞基因表达在肥胖哮喘患者中与正常体重哮喘患者中的差异是由遗传多态性决定的（eQTL和祖先特异性单倍型），并受到DNA甲基化的影响。我们建议如下：具体的目的是解决这些假设：（1）为了量化Th细胞基因表达差异，肥胖哮喘和正常体重哮喘儿童。(2)为了确定表观遗传机制调节肥胖对哮喘的影响。(3)研究基因多态性，包括祖先特异性单倍型，决定肥胖相关哮喘的易感性。Th细胞从100 将年龄和性别相匹配的肥胖哮喘儿童和100名体重正常的哮喘儿童隔离。我们同时进行了a）通过定向转录组进行基因表达的全基因组检测测序（RNA-seq）B）通过HELP-标记的DNA甲基化和c）遗传多态性和单个通过对这些细胞进行基于阵列的基因分型，核苷酸多态性（SNP）提供祖先信息。基因表达与遗传多态性的关联已经确定了预测遗传性的变体。易感性，可用于筛选高危个体。基因表达、DNA甲基化和遗传多态性的验证研究现在将使我们能够确认肥胖哮喘表型的特异性机制分子途径，并改善我们的了解疾病的发病机制。我们将鉴定出与非特应性炎症可能是治疗干预的新靶点。我们的研究将提供对高风险种族中肥胖相关哮喘发病机制的基本见解。作为一名儿科肺病学家，我的目标是成为一名独立的翻译研究者，儿童哮喘，重点关注肥胖对肺部的影响。这K23指导患者导向- 研究职业发展奖允许深入研究遗传和表观遗传因素影响少数民族肥胖哮喘儿童Th细胞介导的炎症反应本提案的结论我为我的R 01基金提供了基础，该基金的重点是进一步调查CDC 42 途径，被确定为在这个K23奖的最高差异表达途径。作为我们未来的目标，我们计划 a）验证患有以下疾病的儿童的单独队列中的关键差异表达和/或甲基化分子：控制不佳的疾病B）证实关键分子在体外细胞培养系统中的作用，特异性抑制剂和/或甲基化调节剂c）对以下之间的联系进行前瞻性研究：肥胖的发病、体重增加的速度、哮喘的发展和Th细胞分化，肥胖相关的哮喘折磨着城市儿童。本申请中提出的职业发展计划纳入了a）来自已建立的表观基因组学、肥胖相关疾病、T细胞生物学、哮喘和粘膜和系统免疫，B）遗传学和表观基因组学课程，以及新方法的实践培训，研究基因表达、基因分型和DNA甲基化，以及c）参与和介绍当地，区域和国家会议。总之，K23奖中提出的研究为我的研究奠定了基础。发展成为儿童肥胖相关哮喘领域的独立研究者。我现在我专注于在这个基础上，通过验证我们的发现，随后将这些结果用作进一步研究遗传易感性对儿童肥胖的影响的初步数据- 相关哮喘

项目成果

期刊论文数量（24）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Comparison of severity of asthma hospitalization between African American and Hispanic children in the Bronx.

DOI：
10.1080/02770903.2019.1609981
发表时间：
2020-07
期刊：
The Journal of asthma : official journal of the Association for the Care of Asthma
影响因子：
0
作者：
Lee DS;Gross E;Hotz A;Rastogi D
通讯作者：
Rastogi D

Association of fractional exhaled nitric oxide with asthma morbidity in urban minority children.

城市少数民族儿童呼出一氧化氮分数与哮喘发病率的关系。

DOI：
10.1080/02770903.2022.2073549
发表时间：
2023
期刊：
The Journal of asthma : official journal of the Association for the Care of Asthma
影响因子：
0
作者：
Chen,Laura;Agalliu,Ilir;Roth,Adam;Rastogi,Deepa
通讯作者：
Rastogi,Deepa

Contribution of systemic and airway immune responses to pediatric obesity-related asthma.