Th17细胞表面CX3CR1在慢性肾脏病相关动脉粥样硬化中的作用及机制研究

T cell immunity plays an important role in atherosclerosis induced by chronic kidney disease (CKD). Our former research indicated that T cell CX3CR1 mediated T cell recruitment and plaque formation of aorta in mouse with chronic kidney impairment. However, it remains unclear which subset of T cells is most critical. A late study showed Th17 cell mediated excess atherosclerotic inflammation in CKD. Accordingly we hypothesize that Th17 cell surface CX3CR1 induces chemotaxis of Th17 cell and atherosclerosis in CKD and interaction between CX3CL1-CX3CR1 axis and IL-17a is probably involved in the process. Based on our previous study, we will discuss the role of Th17 cell CX3CR1 in modulation of CKD related atherosclerosis and its molecular mechanism at animal and cellular level, and provide experimental evidence for further research on new strategy of intervention in CKD related atherosclerosis.

T细胞免疫在慢性肾脏病（CKD）相关动脉粥样硬化发生中发挥了重要的调节作用。申请者既往的研究表明：慢性肾脏病小鼠模型中，T细胞表面CX3CR1在介导T细胞趋化至主动脉处并导致动脉粥样斑块形成中起到了重要作用，但具体是何种T细胞亚群表面的CX3CR1发挥关键作用我们并不清楚。近年来有研究表明，Th17细胞介导了CKD相关动脉粥样硬化的发生。我们推测是Th17细胞表面CX3CR1介导了CKD中Th17细胞向小鼠主动脉的趋化并导致动脉粥样硬化形成，该过程中CX3CL1-CX3CR1轴和Th17细胞分泌的IL-17a相互作用为其可能机制。本研究在申请者前期的工作基础上，拟应用小鼠过继移植（adoptive transfer）实验、细胞趋化实验等方法，分别从动物和细胞层面探讨Th17细胞表面CX3CR1在CKD相关动脉粥样硬化中的调控作用和分子机制，为探索干预CKD相关动脉粥样硬化的新策略提供依据。

动静脉内膜增殖导致的动静脉內瘘失功是维持性血液透析患者的常见严重并发症，但其分子机制目前尚不明确。本研究发现CX3CL1可以促进小鼠平滑肌细胞分泌CX3CR1，CX3CL1-CX3CR1轴有促进小鼠平滑肌细胞增殖的趋势，CX3CL1-CX3CR1轴可以显著减少小鼠平滑肌细胞的凋亡并且明显增强小鼠平滑肌细胞的迁移能力。项目组后期计划在单肾切除的动静脉內瘘小鼠模型中对CX3CL1-CX3CR1轴在內瘘内膜增殖中的作用进行探索。本研究为探讨动静脉內瘘中内膜增殖的分子机制提供了一定理论基础，若实验假设能进一步在动物模型中得以验证，则可能为防治动静脉內瘘内膜增殖导致的动静脉內瘘失功提供有力科学依据。