化瘀清热利湿法靶向Jak/STAT信号通路调节DC功能干预DVT作用与关键机制研究

Deep vein thrombosis (DVT) does serious harm for patients’ health, and the development of theraputic method is meaningful in this field. The pathogenesis of DVT is multiple, and the immunologic mechanism is a hot point in recent years. In our previously study, it was found that T-cell paradigm shift is involed in DVT; however, the initial factor and mechanism of this phenomenon remain unclear. Dendritic cells (DCs) play a vital role in initiating and regulating T-cell immune response, and Jak/STAT signaling pathway is cricial for development of DC’s differentiation and funcuntion. Accoding to the leading edge of communication between DCs and T-cells, and base on the findings of our pre-experiment that there is dysfunction of DC in DVT mice and the TCM method of Huyuqingrelishi has regulatory effect on it, it was hypothesized that the subsets differentiation and funcion of DCs are involved in the T-cell subsets shift in DVT, and DCs may be the effective therapeutic target of the TCM method of Huyuqingrelishi for treating DVT. The current research will focus on the pathogenic role of DC in DVT and the regulatory effect of Huyuqingrelishi on it via targeting Jak/STAT signaling pathway. The findings of the current research will further elucidate the immunologic mechanism of DVT, enrich the scientific meaning of “Yure Theory” in TCM, and offer novel therapeutic method and target for the clinic.

发掘深静脉血栓（DVT）有效治疗方法的难点在于其发病机制的复杂性，其中免疫机制是研究热点之一。本项目在前期创新性发现DVT中T细胞亚群失衡与血管内皮细胞（VEC）损伤和DVT病情演变密切相关，并被化瘀清热利湿中药逆转基础上，拟重点探讨T细胞失衡的始动因素和药物作用靶点。根据DVT小鼠存在树突状细胞（DC）亚群失衡、化瘀清热利湿中药调控Jak/STAT信号通路而影响DC亚群功能等预实验结果，结合DC启动并调控T细胞分化与应答免疫学理论，推测DC功能改变是DVT中T细胞亚群失衡的根源和化瘀清热利湿法干预的靶点。重点探讨DVT中DC对T细胞失衡的影响、Jak/STAT信号通路对DC的调控，以及化瘀清热利湿法通过Jak/STAT途径调控DC的作用。预期结果将阐释化瘀清热利湿法靶向Jak/STAT信号通路调节DC功能治疗DVT的关键机制，丰富中医学“瘀热病机理论”科学内涵，为治疗提供新的靶点与途径。

深静脉血栓形成（DVT）是常见的周围血管疾病，其急性期肺栓塞并发症是常见急性致死原因，慢性期则多见静脉瓣膜破坏所导致的患肢肿胀、淤积性皮炎、顽固性小腿溃疡等后遗症。传统西医治疗DVT手段主要包括抗凝、溶栓等方法，但存在过敏、出血等严重副作用以及价格昂贵等缺点。中医药治疗虽然具有毒副作用小、价格低廉等优点，但是其治疗的物质基础、作用靶点和分子机制尚不明确。本研究在国家自然科学基金面上“化瘀清热利湿法靶向 Jak/STAT 信号通路调节 DC 功能干预 DVT作用与关键机制研究（No.81673981）”资助下，以树突状细胞（DC）分化与功能为切入点，观察化瘀清热利湿法靶向Jak/STAT信号通路调节DC功能干预DVT作用与关键机制研究，进一步阐释中医学“瘀热互结”病机理论科学内涵，为临床治疗提供新的靶点与途径。研究内容及创新点包括：1、证实DC亚群（pDC/cDC）及T细胞亚群偏移导致血管内皮细胞损伤参与了DVT形成与发展，调控DC与T细胞亚群分化和功能可能成为治疗DVT的有效途径。2、化瘀清热利湿中药消栓通脉汤靶向Jak/Stat信号通路，调控pDC/cDC亚群分化，逆转DC亚群及功能失衡，降低DC表面MHC-II分子、共刺激分子及功能性分子表达，保护血管内皮功能，进而治疗DVT。3、发现非编码RNA异常表达导致的细胞因子失衡参与了DVT形成与发展，调控非编码RNA重塑细胞因子稳态可能成为治疗DVT的有效靶点。4、研究成果为阐释中医学“瘀热互结”病机理论提供了实验室依据，丰富了中医学“瘀热互结”理论的科学内涵。 .研究成果申请国家发明专利4项，发表学术论文9篇，其中SCI收录5篇、中文核心期刊论文4篇；参加会议交流十余次，其中国际会议交流2次；培养齐鲁卫生与健康杰出青年人才1名、博士后出站1名、硕士研究毕业2名、硕士研究生在读2名；获得山东省中医药科技一等奖1项；在此基础上获得中国博士后特别资助、山东省重点研发计划资助各一项。部分工作正在投稿或审稿中，后续工作将标注基金号并及时向基金委汇报。