锌指蛋白A20负调控宫内生长迟缓致成年期哮喘的作用机制

There is evidence that intrauterine growth retardation (IUGR) or low birth weight is strongly correlated with an increased risk of asthma later in life. Furthermore, epigenetics plays an important role in the development of asthma following IUGR. Additionally, increased zinc finger protein A20 has a protective role in the development of asthma during exposure to farm environment in childhood. Our previous study revealed that A20 expression significantly down-regulated in rat lung tissue from IUGR group. Hence, we propose a hypothesis that IUGR can cause the decrease of A20 gene expression, thereby weakening the inhibition of NF-κB and increasing the release of inflammatory mediators. This would induce IUGR individuals to be highly sensitive to allergens, resulting in the occurrence of asthma. Furthermore, RNA methylation modification could be an important regulatory mechanism and maintained throughout the life. The present study would investigate the role of A20 in asthma induced by IUGR, and to explore whether overexpression of A20 in IUGR individuals could reduce the risk of IUGR-related asthma later in life. The study would provide a new direction in the prevention and treatment of asthma in childhood or adulthood, and provide a new theoretical basis for controlling the fetal origins of adult disease, which could have an important clinical significance.

本课题针对宫内生长迟缓（IUGR）或低出生体重儿的个体在成年后有增加的哮喘风险，表观调控在IUGR致哮喘的发病中起重要作用，而增加的锌指蛋白A20表达在儿童期农场环境的暴露对哮喘保护作用中有重要作用，结合前期发现A20在IUGR大鼠肺组织表达下降，率先提出IUGR可导致A20基因表达下降从而减弱对NF-κB的抑制作用导致哮喘相关的炎症介质释放，引起IUGR个体对过敏原等外界刺激高度敏感从而诱发哮喘的假说；而RNA甲基化修饰可能是A20表达下降的重要调控机制并可以持续存在。本课题探讨了A20在IUGR诱导的成年期哮喘中的作用，同时亦探讨IUGR个体通过气管内给药过表达A20是否能保护生命后期哮喘发生的风险。本研究对阐明胎儿来源的哮喘发生的调控机制具有重要意义，可望为儿童和成人哮喘的预防和治疗提供新的思路，并为胎儿来源的成人疾病的控制提供新的理论依据。

大量的临床与流行病学证据已经证实宫内生长迟缓（IUGR）个体在生命后期有增加的哮喘风险，表观调控在IUGR致哮喘的发病中起重要作用。先前的研究也揭示增加的锌指蛋白A20表达在儿童期农场环境的暴露对哮喘保护中的重要作用，结合A20在IUGR肺组织表达下降，我们提出IUGR可导致A20基因表达下降从而引起IUGR个体对过敏原刺激高度敏感从而诱发哮喘的假说。本课题旨在研究IUGR能否引起肺组织A20基因表达下降，而下调的A20将减弱对下游通路的抑制作用导致哮喘相关炎症介质的释放，从而引起个体对OVA高度敏感，导致气道的高反应性而诱发更加显著的哮喘变化；以及A20基因的表达降低是否与表观修饰相关，特别是RNA甲基化修饰，并且这种修饰能否终身维持。在目前的项目中，我们研究发现IUGR可诱导A20基因表达下降，导致A20涉及的泛素化蛋白表达改变，包括增加的泛素化Histone H3、Ywhag蛋白、DDI2蛋白以及降低的泛素化Lysozyme、Moesin等蛋白；A20基因的表观调控特别是RNA甲基化修饰增加是A20表达下降的重要调控机制并可以持续存在。而且气道A20过表达可减轻IUGR大鼠对OVA的激发反应，进一步支持A20在IUGR致哮喘中的作用。本研究对阐明胎儿来源的哮喘发生的调控机制具有重要意义，可望为儿童和成人哮喘的预防和治疗提供新的思路，并为胎儿来源的成人疾病控制提供新的理论依据。