CLEC2-PDPN调控扰动流诱导的血小板-单核细胞聚集体内皮下迁移的分子机制及转化研究

动脉粥样硬化（AS）的重要发病机制之一是炎症，通常起始于血流扰动的动脉分支或弯曲处。最新研究表明血小板通过影响单核细胞的迁移和巨噬细胞的极化参与调控斑块的形成。我们前期研究也发现，在扰动流作用下血小板与单核细胞同时沉积于血管内皮下，且血小板Clec2敲除或髓系细胞Pdpn敲除均可阻止该过程。然而，CLEC2-PDPN调控扰动流诱导的血小板-单核细胞聚集体（PMA）形成、向内皮下迁移的作用和机制尚不清楚。因此，本课题将：1）基于小鼠扰动流模型，时空解析PMA形成、血小板和单核细胞的活化及迁移的过程；2）通过血小板Clec2敲除或单核细胞Pdpn敲除研究PMA形成及内皮下迁移的影响及分子机制；3）利用小鼠AS模型，研究血小板Clec2敲除或单核细胞Pdpn敲除对斑块形成的影响，及靶向PDPN对斑块的作用效果。我们的研究将阐明血小板在扰动流作用下参与血管炎症、调控AS斑块形成的新的细胞分子机制。

One of the most important pathogenesis of atherosclerosis is inflammation, which usually occurs at the branch or bend of the artery where the blood flow is disturbed. Recent studies have shown that platelets participate in the regulation of plaque formation by affecting the monocyte migration and the macrophage polarization. Our previous study also found that under disturbed flow, platelets and monocytes coexist in the subendthelium, which was prevented in platelet specific Clec2 knockout or myeloid specific Pdpn knockout mice. However, the role and mechanism of CLEC2-PDPN regulation in the formation and migration of platelet-monocyte aggregates induced by d-flow is unclear. Therefore, this project will first analyze spatiotemporally the progression of PMA formation, and the activation and migration of platelets and monocytes based on in vivo disturbed flow model in mouse. Secondly, the effects and molecular mechanisms of PMA formation and subendothelial migration will be studied by platelet specific Clec2 knockout or monocyte specific Pdpn knockout mice. Finally, combing with mouse AS model, the effects of platelet CLEC2 or monocyte PDPN deletions as well as PDPN blocking on the plaque formation will be investigated. Our study will elucidate the new cellular and molecular mechanisms by which platelets participate in vascular inflammation and the regulation of the atherosclerotic plaque formation under disturbed flow.