circTAB2通过RanBP2/NLRP3调控树突状细胞维持肝脏免疫稳态在自身免疫性肝炎中的机制

经典型树突状细胞（cDCs）异常活化导致的肝脏免疫稳态失衡是自身免疫性肝炎（AIH）发病的重要环节。我们前期将AIH患者的cDCs深度测序，筛选并鉴定了一个表达明显下调的新的环状RNA即circTAB2；过表达circTAB2可通过RanBP2（SUMO连接酶）抑制cDCs的活化且可调控NLRP3的SUMO化水平。据此，我们提出“circTAB2通过RanBP2介导NLRP3的SUMO化修饰调控cDCs维持肝脏免疫稳态参与AIH发病”的假说。本项目拟通过临床样本及体内外实验扩大验证circTAB2和RanBP2在AIH患者和小鼠、体外成熟的cDCs中的表达及临床相关性，用质谱、RNA pull down等实验探明circTAB2对RanBP2的具体作用机制，并验证过表达circTAB2的cDCs对AIH小鼠的治疗作用，以证实该假说。藉此，丰富和完善AIH的发病机制理论，为其治疗提供新策略。

Disruption of hepatic immune homeostasis induced by aberrant activation of conventional dendritic cells (cDCs) plays a pivotal role in the pathogenesis of autoimmune hepatitis (AIH). We have identified a novel circRNA named circTAB2 in cDCs using high-throughput sequencing, which was down-regulated significantly in AIH patients. Overexpression of circTAB2 inhibited the activation of cDCs via Ran binding protein 2 (RanBP2), a small ubiquitin-like modifier (SUMO) E3 ligase, and also modulated nucleotide binding oligomerization domain-like receptor protein 3 (NLRP3) SUMOylation. Considering the effects of circTAB2 on RanBP2, we hypothesized that "circTAB2 maintains hepatic immune homeostasis in AIH by regulating dendritic cells via RanBP2/NLRP3". We will firstly detect the expression of circTAB2 and RanBP2 in mature and immature cDCs from AIH patients and mice both in vivo and in vitro. Besides, we will verify the molecular mechanisms of circTAB2 on RanBP2 by mass spectrometry and RNA pull down, etc. Finally, the therapeutic potential of circTAB2 in AIH mice will also be investigated to pave the way for a new treatment target. Taken together, our research will provide a new insight into the mechanism of cDCs in the pathogenesis of AIH and will facilitate the development of new therapies for AIH.