DUSP5通过促进巨噬细胞泡沫化导致动脉粥样硬化进展的作用以及机制研究

动脉粥样硬化（AS）的发病机制尚未明确，发现AS新型分子标志及其作用机制，能为AS的诊治提供重要的理论和实践指导。通过分析人早期以及进展期颈动脉斑块芯片，并收集行颈动脉内膜剥脱术病人斑块予以验证，发现双特异性磷酸酶5（DUSP5）在进展期斑块中显著升高，且DUSP5高表达同巨噬细胞相关，降低DUSP5的表达可以显著降低凝集素样氧化型低密度脂蛋白受体1(LOX-1)表达而减少巨噬细胞内脂质含量。对DUSP5相互作用的蛋白进行分析，发现核内异粘蛋白（MTDH）可能是其潜在的下游调控分子。本项目旨在前期研究基础上探讨DUSP5作为AS标志物可靠性；通过髓系移植DUSP5基因敲除（DUSP5-/-）小鼠骨髓于ApoE-/-小鼠中，在体内验证髓系特异敲除DUSP5可显著抑制动脉粥样硬化进展；探讨DUSP5导致动脉粥样硬化进展的分子机制及信号通路。本研究有望为AS寻找新的标志物以及诊治靶点。

The pathogenesis of atherosclerosis (AS) remains unclear. Identifying the molecular marker and target of AS is beneficial for the diagnosis and treatment of AS. Through investigating the microarrays of early and advanced phases of atherosclerosis plaques, we found dual-specificity phosphatases 5 (DUSP5) was significantly elevated in the advanced carotid plaques. Besides, the elevated DUSP5 expression was positively correlated with macrophages. Meanwhile, the results were validated in the plaques collected in the patients underwent carotid endarterectomy in Sir Run Run Shaw hospital. Silencing DUSP5 activity in vitro could significantly decrease lipid content in macrophages through inhibiting lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1). Furthermore, protein-protein interaction database analysis revealed that MTDH was the downstream candidate target of DUSP5. In this proposed project, we are aiming to establish DUSP5 as a novel biomarker of AS, to validate the role of DUSP5 in AS progression in vivo using mouse models, and to uncover the molecular mechanisms and signaling pathways that are involved in DUSP5-promoted AS progression. This study holds the promise for identifying new diagnosis makers and therapeutic targets of AS.