E3泛素连接酶HUWE1在免疫性血小板减少性紫癜Treg/Th17免疫失衡中的作用及机制研究

免疫性血小板减少性紫癜（immune.thrombocytopenia，ITP）是以血小板减少和皮肤粘 膜出血为特征的自身免疫性疾病，Treg/Th17失衡发挥重要作用，但具体分子机制不清楚。前 期研究显示，ITP患者外周血CD4+T细胞中E3泛素连接酶HUWE1的表达增加；干扰HUWE1部分恢复 Treg/Th17平衡；HUWE1既是miR-125a-5p调控的靶分子，也可介导Ets-1的泛素化降解。由此 我们推测，miR-125a-5p表达下降使得HUWE1增加，降低Ets-1水平，在ITP发病中发挥重要作用。本项目重点研究：1）HUWE1在ITP.Treg/.Th17失衡中的作用；2）HUWE1促进Ets-1泛素化 降.解的具体机制；3）miR-125a-5p对HUWE1的调控情况。本项目的完成有助于阐明HUWE1在IT P患者Treg和Th17失衡中的内在机制，并提供一个直接的治疗靶点。

Immune thrombocytopenia (ITP) is an organ-specific autoimmune disease, characterized with decreased platelet count and increased bleeding risk. It is well known that Treg/Th17 imbalance plays an important role in ITP development. However, the molecular mechanism of Treg/Th17 imbalance in ITP is unclear. Our preliminary results showed that ubiquitin E3 ligases HUWE1 was significantly increased in CD4+T cells from ITP； Downregulation of HUWE1 could partially.improved Treg/Th17 balance in ITP； Further study showed that HUWE1 could directly interact with Ets-1 and mediated Ets-1 ubiquitylation and degradation. In.addition, HUWE1 was the target of miR-125a-5p in CD4+T cells. As a result, we speculated that downregulation of miR-125a-5p contributed to the increase of HUWE1 expression, which resulted in the decrease of Ets-1expression in CD4+T cells from ITP..The project intends to study 1）the role of HUWE1 in Treg / Th17 immune imbalance of immune thrombocytopenic purpura; 2) the specific mechanism of HUWE1 promoting Ets-1 ubiquitination degradation; 3) miR -125a-5p on the target gene HUWE1.We will further explore the molecular mechanism of HUWE1 on imbalance of Treg/Th17 imbalance, trying to provide a potential target for the treatment of ITP in the future.