糖皮质激素受体通路在先天性纯红再障发生和治疗中的作用及机制研究

Diamond Blackfan Anemia（DBA）is a kind of inherited bone marrow failure syndrome(IBMFS) characterized by obvious paucity of erythroid progenitors in bone marrow while other linages are normal. Haploinsufficiency due to mutation of ribosome proteins gene participates in the pathogenesis of DBA. However the pathogenetic mechanism of DBA was still unkonwn. Glucocorticoid is the dominate drug of DBA. Glucocorticoid receptor(GR) signaling pathway plays a crucial role in the development of erythroid, especially the stages which are the key stage in the pathogenesis of DBA. RNA-seq of 9 DBA patients in our lab dispalyed that many genes in GR signaling pathway were abnormally expressed. The pathogenetic and pharmacological mechanism of GR signaling in DBA require intensive study. This project plans to use the next generation sequencing in combination with Flow cytetometry, induced pluripotent stem cells technology and in vivo aniaml model to investigate the function of GR signaling in DBA and erythroid development, to explore the pharmacological mechanism of glucocorticoid treatment failure in DBA, and to screen out specific small molecule drugs targeting GR signaling. Our study will help to uncover the pathogenetic mechanism of DBA and improve the curative ratio of DBA.

先天性纯红细胞再生障碍性贫血（Diamond Blackfan Anemia，DBA）是一种罕见的先天性骨髓衰竭综合征，以骨髓增生正常而早期红系祖细胞明显减少为主要特征，是研究红系早期发育的良好疾病模型。目前认为DBA发病与核糖体蛋白突变相关，但机制尚不明确。糖皮质激素是治疗DBA的主要药物。糖皮质激素受体（glucocorticoid receptor，GR）信号通路参与红系祖细胞发育过程。我们对9例DBA患儿骨髓标本进行RNA-seq检测后发现，GR通路的多种基因在DBA患儿中异常表达。本课题拟从DBA患儿标本出发，结合流式分选和微量细胞测序技术，利用诱导多能性干细胞及体内小动物实验模型，挖掘GR信号通路在红系发育不同阶段和DBA发生中的作用及功能，揭示GR信号通路在DBA发生和糖皮质激素治疗无效中的分子机制，据此设计靶向小分子药物，优化现有治疗方案，提高DBA的诊疗水平。