不规则趋化因子（Fractalkine）在大动脉炎发病机制中的关键作用及其机制研究

Takayasu's arteritis is a subtype of large vessel vasculitis characterized with pathologically chronic granuloma formation and demographically preferential distribution in Asian groups.The underlying pathogenesis of Takayasu's arteritis maintains in uncertainty.Our reasearch group studied a significant improvement of serum Fractalkine level in Takayasu's arteritis patients compared with healthy controls,through screening assisted by high-througout protein chips and subsequently confirmation experiments.We operated bioformatic analysis and then found that Fractalkine and its receptor CX3CR1 bear a large possibility to play an irreplaceable rule in pathogenesis of Takayasu's arteritis.Therefore, we propose a hypothesis that Fractalkine/CX3CR1 could recruit macrophages and T lymphacytes subsets, which are then activated to release cytokines such as IFN-γ，TNF-α and MIP-1α,participating in the pathgenesis of Takayasu's arteritis.To buttress this hypothesis,we are programmed to investigate the potential role and underlying mechanisms of Fractalkine in Takayasu's arteritis on cellular,tissue and animal levels through following methodologies:flow chemistry,Transwell assay/cell migration assay,animal models with Fractalkine overexpression specifically in vascular endothelial cells,CX3CR1-GFP labeled cell transplantation,immunofluorescence co-localization analysis and animal PET/CT.On the other hand,we will explore the function of anti-Fractalkine antibodies in the therapy of Takayasu's arteritis.This study is important for future diagnosis,therapy and medicine development targeting the pathogenesis of Takayasu's arteritis.

大动脉炎为一类亚洲人群高发的慢性肉芽肿性大血管炎，其发病机制尚未明确。本课题组前期通过高通量蛋白芯片筛查和重复验证发现大动脉炎患者外周血浆中Fractalkine水平显著升高，生物信息学分析提示Fractalkine及其受体CX3CR1可能是大动脉炎发病的关键通路。我们提出假说：Fractalkine可能通过招募巨噬细胞及T细胞亚群，活化并释放IFN-γ、TNF-α等细胞因子参与大动脉炎发生发展。本研究首先从细胞、组织、动物水平，通过流式细胞分选、体外趋化实验、免疫荧光共定位、构建Fractalkine血管特异过表达动物模型、小动物PET/CT、CX3CR1-GFP标记细胞移植等技术，阐明Fractalkine在大动脉炎发病中的关键作用。进而，我们进行Fractalkine抗体治疗大动脉炎的临床先导性研究，寻找新的治疗靶点。研究结果将为大动脉炎早期诊断、治疗及药物研发奠定坚实基础。

大动脉炎为一类亚洲人群高发的慢性非特异性大血管炎 其发病机制尚未明确。本课题组通过高通量蛋白芯片筛查和重复验证发现大动脉炎患者外周血浆中Fractalkine水平显著升高，生物信息学分析提示Fractalkine及其受体CX3CR1可能是大动脉炎发病的关键。针对大动脉炎患者的宏基因组测序鉴定到大动脉炎和对照组差异菌。其中10种差异菌种可以有效区分大动脉炎患者组和对照组，其训练集、测试集及独立队列验证AUC分别为82.1%, 98.0% 和 94.8%。第三，本研究针对大动脉炎儿童和成人队列的回顾性分析了显示心衰，卒中和BMI均为影响预后的独立危险因素。PET-CT作为一种新的影像学诊断措施，在大动脉炎的早期诊断中发挥作用。本研究结果将为大动脉炎早期诊断、治疗及药物研发奠定坚实基础。