DNA methylation in children hospitalized with asthma exacerbation

描述（由申请人提供）：儿童哮喘控制不佳导致反复加重和住院。哮喘急性发作标准治疗的反应在住院儿童中是异质的，并且相当一部分患者对治疗反应较差。我们的长期目标是了解不同治疗反应的分子机制，并确定可靠的相关生物标志物。该R21应用的目的是确定鉴定与不同治疗相关的特征性甲基化特征的可行性，这是实现我们长期目标的一步 哮喘急性发作住院儿童的反应组。我们的中心假设是：1）哮喘儿童的DNA甲基化谱受标准哮喘急性发作治疗的影响，导致基因失调; 2）这些甲基化谱与哮喘儿童对治疗的不同临床反应相关。为了验证我们的假设，我们建议检测哮喘急性发作住院儿童鼻上皮细胞基因组中超过460万个CpG位点的DNA甲基化状态，并确定其与基因表达水平和患者临床表型的相关性。拟议研究的预期结果包括：1）鉴定具有DNA甲基化变化的基因，作为哮喘发生和加重的潜在促成因素; 2）鉴定与不同临床治疗反应相关的DNA甲基化标志物，为未来旨在使用基因组和表观基因组谱预测因哮喘加重住院儿童的治疗反应的研究奠定基础。这项探索性R21中提出的研究具有重要意义，因为它将通过开发更个性化的哮喘急性发作治疗方案产生积极影响。与对治疗反应差相关的特征性DNA甲基化标记可用于识别可能需要替代或额外治疗策略的住院哮喘儿童。此外，它将确定这些“不良反应者”中的关键基因和途径，这些基因和途径可能是这一亚类患者干预的最佳靶点。

DESCRIPTION (provided by applicant): Poorly controlled asthma in children results in repeat exacerbations and hospitalization. The response to standard treatment for asthma exacerbation is heterogeneous among hospitalized children and a significant subset of patients responds poorly to therapy. Our long-term goal is to understand the molecular mechanisms for diverse treatment responses and identify reliable associated biomarkers. The objective of this R21 application, which is a step towards attainment of our long-term goal, is to establish the feasibility of identifying characteristic methylation signatures associated with distinct treatment response groups among children hospitalized with asthma exacerbation. Our central hypothesis is 1) DNA methylation profiles in asthmatic children are subject to alteration by standard asthma exacerbation treatment, resulting in gene dysregulation; and 2) these methylation profiles are associated with distinct clinical responses to treatment among asthmatic children. To test our hypothesis, we propose to assay DNA methylation status at more than 4.6 million CpG sites across the genome in nasal epithelial cells from children hospitalized with asthma exacerbation, and determine their correlation with gene expression levels and patients' clinical phenotypes. Expected outcomes of the proposed studies include 1) the identification of genes with DNA methylation changes as potential contributing factors to asthma development and exacerbation; and 2) the identification of DNA methylation markers correlated with distinct clinical treatment response, laying the ground for future studies designed to predict treatment response in children hospitalized with asthma exacerbation using genomic and epigenomic profiles. The research proposed in this exploratory R21 is significant because it would have a positive impact by enabling the development of more personalized treatment options for asthma exacerbation. The characteristic DNA methylation signatures associated with poor response to therapy can be used for identifying hospitalized asthmatic children who may need alternative or additional treatment strategies. Furthermore, it will identify critical genes and pathways in these "poor responders" that may be the most optimal targets for intervention for this subcategory of patients.