非典型趋化因子受体CCRL2在深静脉血栓中的作用和机制研究

深静脉血栓（DVT）与炎症密切相关，趋化因子及受体在其中发挥重要作用，但非典型趋化因子受体不能介导胞内信号，尚无有关参与DVT的报道。我们前期研究发现C-C趋化因子受体样蛋白2（CCRL2）受扰动流调控并在血栓段静脉内皮表达上调，血栓中CCRL2与配体chemerin/CMKLR1共定位，敲除CCRL2显著减少血栓巨噬细胞浸润和血栓大小并加速再通，提示CCRL2可能是DVT发生发展过程中的关键调控分子。进一步发现，chemerin、CMKLR1与巨噬细胞和血小板共定位。据此提出假说：内皮细胞在异常血流动力学作用下上调CCRL2表达，通过chemerin/CMKLR1途径放大炎性效应、调控凝血过程，进而调控DVT的形成和再通。为证实以上假设，本课题将采用系列的生理、生化学等分析方法，结合动物模型和临床样本，系统研究CCRL2在DVT炎症和凝血过程中的作用和调控机制，提出防治DVT的新策略。

Deep vein thrombosis (DVT) is tightly related to inflammation, and chemokines and receptors play an important role in the process. Nevertheless, it has not been clear whether atypical chemokine receptors, which are unable to mediate intracellular signaling, participate the development of DVT. Our previous study found that C-C chemokine receptor-like protein 2 (CCRL2) is regulated by disturbance flow and up-regulated in the venous endothelium of the thrombus segment. CCRL2 is co-localized with the ligand chemerin/CMKLR1 in the thrombus and knockout of CCRL2 reduces thrombus macrophage infiltration and thrombus size, and accelerates DVT recanalization. These results suggest that CCRL2 may be a key regulatory molecule in the occurrence and development of DVT. It was further discovered that chemerin and CMKLR1 co-localize with macrophages and platelets. On these bases, we put forward research hypothesis: under the influence of abnormal hemodynamics, the expression of CCRL2 is up-regulated in endothelial cells, amplifying the inflammatory response and regulating the coagulation process through the chemerin/CMKLR1 pathway, thereby regulating the formation and recanalization of DVT. In order to confirm the above assumptions, the project will use a series of physiological and biochemical analysis methods, combined with animal models and clinical samples, to systematically study the regulatory role and mechanism of CCRL2 in DVT inflammation and coagulation process, and propose a new strategy for the prevention and treatment of DVT.