The role of TET1 in childhood asthma

TET1 在儿童哮喘中的作用

• 批准号: 9055643
• 负责人: Hong Ji
• 金额: $ 19.5万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9055643
• 关键词: Adrenal Cortex Hormones; Affect; Allergic; Animal Model; Asthma; Binding; Bronchodilator Agents; Cell Maintenance; Cell physiology; Cells; Child; Childhood; Childhood Asthma; Chromatin Structure; Chronic Disease; Complex; DNA; DNA Methylation; Dendritic Cells; Dependence; Development; Disease; Environment; Environmental Risk Factor; Epigenetic Process; Epithelial; Epithelial Cells; Etiology; Family member; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Transcription; Genomic Imprinting; Genomic Segment; Genomics; Goals; House Dust; Human; Hydroxyl Radical; Hydroxylation; Immune; Inflammatory; Interleukin-1 beta; Lead; Location; Lung; Malignant Neoplasms; Measures; Mental Depression; Methylation; Mus; Nature; Organ; Pathogenesis; Patients; Pattern; Phenotype; Pilot Projects; Play; Population; Protein translocation; Qualifying; Research; Risk; Role; Sampling; Severities; Shapes; Siblings; Solid; Stem cells; Stimulus; T-Lymphocyte; Testing; Therapeutic; Tissues; Variant; Work; airway epithelium; allergic response; asthmatic; base; clinical phenotype; cohort; cytokine; demethylation; drug candidate; epigenetic variation; epigenomics; gene environment interaction; genome-wide; individual patient; innovation; insight; knock-down; novel; oxidation; phenotypic data; promoter; public health relevance; pyrosequencing; relating to nervous system; response; small hairpin RNA; tool; treatment response

 DESCRIPTION (provided by applicant): Asthma is the most frequent chronic disease among children. Although the airway epithelium is a major driver of the allergic responses in the etiology of asthma, no current asthma treatments specifically target the airway epithelium. Standard asthma treatments including bronchodilators and corticosteroids are not completely effec- tive in all asthmatics, especially in those with severe diseases, indicating a great need fo alternative personal- ized asthma therapy. As a DNA demethylase that converts 5mC to 5hmC, the role of TET1 in stem cell maintenance, neural activity and cancer have recently been revealed. However, the role of TET1 in asthma is unknown. From our pilot Exposure Sibling Study, we found that the promoter methylation of TET1 is decreased in asthmatic children compared to non-asthmatics in airway epithelial cells, and this lower methylation level correlates with higher expression levels of TET1. This increase in TET1 expression in asthmatics is also asso- ciated with a significant increase in 5hmC level. Based on these intriguing and novel observations, we hypoth- esize that TET1 contributes to asthma through increasing hydroxyl-methylation of its target genes in the airway epithelium. Our long-term goal is to understand the role of TET1 in asthma pathogenesis and explore its thera- peutic potentials. The objective of this R21 application is to establish the association of TET1 with asthma and to identify its target asthma genes in the airway epithelium, which is a logical step towards a subsequent R01 application aiming to further understand the detailed contributions of TET1 in asthma. Our study will be the first to establish the role of TET1 in regulating asthma genes in airway epithelial cels. Using samples from two in- dependent cohorts and human primary airway epithelial cells, we propose to test our hypothesis using the fol- lowing specific aims: 1) to determine whether TET1 methylation and expression are associated with asthma, 2) to determine the target genomic locations of TET1 in airway epithelial cells. We expect our novel study will demonstrate that TET1 regulates the expression of its target asthma genes through hydroxylation of their pro- moters. The research proposed in this R21 is significant because it will establish the association of TET1 and its product 5hmC with asthma and asthma phenotypes in children and identify their target genes in the airway epithelium. This will open the door for future research aiming to further understand the roles of TET1 and 5hmC in asthma development using animal models and other available tools, which may result in the devel- opment of novel asthma therapy and have broader impact in other diseases related to TET1.

 描述（由申请人提供）：哮喘是儿童中最常见的慢性疾病。虽然气道上皮是哮喘病因学中过敏反应的主要驱动因素，但目前尚无专门针对气道上皮的哮喘治疗。标准的哮喘治疗包括支气管扩张剂和糖皮质激素并不是对所有哮喘患者都完全有效，特别是对那些患有严重疾病的患者，这表明非常需要替代的个体化哮喘治疗。TET 1作为一种DNA去甲基化酶，将5mC转化为5hmC，其在干细胞维持、神经活动和癌症中的作用最近被揭示。然而，TET1在哮喘中的作用尚不清楚。从我们的试点暴露同胞研究中，我们发现，TET1的启动子甲基化降低哮喘儿童相比，非哮喘患者的气道上皮细胞，这种较低的甲基化水平与TET1的高表达水平相关。哮喘患者TET1表达的增加也与5hmC水平的显著增加阿索。基于这些有趣和新颖的观察，我们假设TET1通过增加气道上皮中其靶基因的羟甲基化而导致哮喘。我们的长期目标是了解TET 1在哮喘发病机制中的作用，并探索其治疗潜力。这项R21应用的目的是建立TET 1与哮喘的关联，并确定其靶点。 哮喘基因在气道上皮细胞，这是一个逻辑步骤，后续的R01应用，旨在进一步了解TET1在哮喘的详细贡献。我们的研究将是第一个建立TET1在调节气道上皮细胞哮喘基因中的作用。使用来自两个独立队列的样本和人原代气道上皮细胞，我们提出使用以下特定目标来检验我们的假设：1）确定TET 1甲基化和表达是否与哮喘相关，2）确定TET 1在气道上皮细胞中的靶基因组位置。我们希望我们的新研究将证明TET1通过其启动子的羟基化来调节其靶哮喘基因的表达。R21中提出的研究具有重要意义，因为它将建立TET 1及其产物5hmC与儿童哮喘和哮喘表型的关联，并确定其在气道上皮中的靶基因。这将为未来的研究打开大门，旨在利用动物模型和其他可用的工具进一步了解TET1和5hmC在哮喘发展中的作用，这可能导致开发新的哮喘治疗方法，并对TET1相关的其他疾病产生更广泛的影响。

项目成果

Diesel exhaust and house dust mite allergen lead to common changes in the airway methylome and hydroxymethylome.

• DOI: 10.1093/eep/dvy020
• 发表时间: 2018-07
• 期刊: Environmental epigenetics
• 影响因子: 3.8
• 作者: Zhang X;Chen X;Weirauch MT;Zhang X;Burleson JD;Brandt EB;Ji H
• 通讯作者: Ji H

Pediatric asthma and autism-genomic perspectives.

小儿哮喘和自闭症基因组观点。

• DOI: 10.1186/s40169-015-0078-x
• 发表时间: 2015
• 期刊: Clinical and translational medicine
• 影响因子: 10.6
• 作者: Oh,Sunghee;Ji,Hong;Barzman,Drew;Lin,Ping-I;Hutton,John
• 通讯作者: Hutton,John