β-arrestin1通过调节JAK/STAT信号通路对Crohn's病机制研究

Crohn’s disease(CD) is one of the major type of inflammatory bowel disease (IBD), its incidence and prevalence are on the rise in recent years. Furthermore, its etiology and pathogenesis are still unclear at present. β-arrestin1 is a kind of multifunctional protein involved in G protein-coupled receptor signal pathway. Signal transducer and activator of transcription(JAK/ STAT) signal pathway plays a significant role in the physiological process of cell growth, differentiation, proliferation and immunological regulation function.. The recent research reported that β-arrestin1 is implicated in the pathogenesis of inflammatory and immunological diseases by regulating JAK/ STAT signal pathway, nevertheless, their roles have not been reported in CD。Based on the previous our study associated with IBD , we firstly designed human samples, animal model（including gene knockout mice) and cell culture to clarify the association between them, aimed to seek for specific molecular markers for CD. Furthermore, this study would provide clear theoretical basis for CD and targeted strategy and scientific basis for treatment of CD.

Crohn's病（Crohn’s disease, CD）是炎症性肠病（inflammatory bowel disease，IBD）的主要类型之一，其发病率和患病率均呈上升趋势，具体病因和发病机制迄今不明。β-arrestin1是G-蛋白偶联受体信号通路中起关键作用的多功能蛋白，JAK/STAT信号转导通路是细胞生理过程的关键支点，参与细胞生长、分化以及免疫调节功能。目前有研究表明β-arrestin1通过调节JAK/STAT信号通路参与了炎症性和免疫性疾病的病理生理过程，而在CD中的作用机制无明确研究依据。本研究在前期IBD研究基础上，通过人体样本、动物模型实验探索β-arrestin1通过JAK/STAT信号通路调控参与CD病理生理过程，为CD发病机制提供清晰的理论基础、为CD早期诊断寻找特异性分子标志以及为治疗提供靶向策略和科学依据。

本研究通过建立急性炎症性肠病动物模型，在转录组学和蛋白组学水平检测β-arrestin在炎症性肠病中的表达；同时检测炎症性肠病中炎症因子（包括促炎因子和抑炎因子）的表达；通过β-arrestin基因敲除建立急性炎症性肠病模型，再检测炎症性肠病相关因子的表达（转录组学和蛋白组学）；利用β-arrestin基因敲除模型探讨β-arrestin在肠炎时对肠上皮渗透性和紧密连接的影响，从而了解β-arrestin对肠上皮屏障功能的作用。研究结果表明β-arrestin2在肠炎小鼠结肠组织中mRNA表达、蛋白水平均发现升高；β-arrestin2敲除后肠道炎症细胞浸润明显减少，表明β-arrestin2敲除有助于抑制肠道炎症的发展，同时有利于维持肠道上皮渗透性和紧密连接的稳定性。