妊娠期哮喘通过表观遗传调控子代Treg/Th17发育的研究

The risks of bronchial asthma were determined by genetic and environmental exposure. Various adverse environmental exposure can affect the development and differentiation of T cells and other genes which altered gene phenotype . Fetal immune functions were impaired and the risk of asthma children increased in inttauterine. The study aimed to establish animal model of asthma during pregnancy and observed Th17 and Treg subsets, foxp3 methylation, histone H3 ( H3K9Ac, H3K18Ac, H3K14Ac) and H4 ( H4K5Ac, H4K8Ac, H4K12Ac ) acetylation status of gestational asthma rats and their offspring. The study discusses epigenetic modification mechanism of Treg / Th17 immunity and provides new theoretical basis of etiology and prevention of asthma.

支气管哮喘的发病风险由遗传和环境暴露相互作用决定，妊娠时，宫内各种不良环境的暴露，可影响胚胎的发育分化过程中T细胞和其他基因出现遗传表观修饰从而改变基因表达，给胎儿免疫功能带来各种影响，导致子代哮喘风险增加。本项目建立妊娠期哮喘动物模型，观察妊娠哮喘大鼠及其子代在发育过程及成年后发病中Th17和Treg亚群分布，Foxp3的甲基化水平，组蛋白H3K4me3、H3K9me2、H3K27me3甲基化状态，组蛋白H3（H3K9Ac、H3K18Ac、H3K14Ac）和H4（H4K5Ac、H4K8Ac、H4K12Ac）乙酰化状态变化，从表观遗传学角度探讨妊娠哮喘对子代发育过程中Treg/Th17免疫中DNA甲基化和组蛋白甲基化、乙酰化之间的相互联系的表观遗传修饰作用机制，为哮喘发病的病因和早期预防提供新的理论依据。

支气管哮喘的发生与遗传有关，母代宫内各种不良环境的暴露，可影响胚胎的发育分化过程中T细胞和其他基因中出现遗传表观修饰从而改变基因表达，给胎儿免疫功能带来各种影响。本实验研究了妊娠哮喘大鼠及其子代发育经历，从Foxp3基因DNA甲基化和组蛋白H3K4me3、H3K9me2、H3K27me3甲基化状态， Foxp3基因组蛋白H3（H3K9Ac、H3K18Ac、H3K14Ac）和H4（H4K5Ac、H4K8Ac、H4K12Ac）乙酰化状态变化两种表观遗传修饰机制入手，以经典的DNA去甲基化药物5-Aza去除上述基因启动区的DNA甲基化，研究发现哮喘大鼠妊娠甲基化平衡模式可被打破，母代与子代均出现Treg与T17的表达失衡，Foxp3蛋白表达水平明显增多，Foxp3基因的甲基化与组蛋白H3K4me3、H3K9me2、H3K27me3甲基化状态明显增加，Foxp3基因组蛋白H3（H3K9Ac、H3K18Ac、H3K14Ac）和H4（H4K5Ac、H4K8Ac、H4K12Ac）过度去乙酰化，给予5-Aza干预后，妊娠哮喘大鼠及其子代Foxp3基因的甲基化水与组蛋白H3K4me3、H3K9me2、H3K27me3甲基化状态平下降，提示妊娠期哮喘对子代Treg/Th17有表观遗传修饰作用，通过改变Treg细胞的表观遗传为子代早期哮喘遗传发病提供新的理论基础和治疗靶点。