Par3L通过调控M1/M2巨噬细胞极化促进动脉粥样硬化的作用及机制研究

调控M1/M2巨噬细胞极化是防治动脉粥样硬化(Atherosclerosis, As)的重要策略，但其机制尚未完全阐明。研究表明Par3L是哺乳动物特有的极性蛋白，只表达在动物组织的极少数细胞中。除了维持乳腺干细胞干性、促进结直肠癌细胞增殖，Par3L的其他病理生理作用并不清楚。本课题组前期发现Par3L不仅在巨噬细胞中表达，且被oxLDL上调；As病变处M1巨噬细胞高表达Par3L；后证实敲低Par3L抑制M1巨噬细胞极化，并促进M2巨噬细胞极化。由此，我们推测oxLDL通过上调Par3L促进M1巨噬细胞极化，并抑制M2巨噬细胞极化，导致As。本项目拟利用巨噬细胞特异性敲除Par3L小鼠，采用免疫荧光、RNA测序、免疫共沉淀、质谱等技术，结合人As样本，揭示oxLDL通过上调Par3L调控M1/M2巨噬细胞极化致As的全新分子机理，为As防治提供潜在药物作用靶点。

Regulation of M1/M2 macrophage polarization is an important strategy for the prevention and treatment of atherosclerosis (As). Partitioning defective 3-like protein (Par3L) is a mammalian-specific polarity protein and expressed in a very small number of cells of animal tissues. Par3L has been shown to maintain breast stem cells and promote colorectal cancer cell proliferation, however, the other pathophysiological function of Par3L remains elusive. Our preliminary data showed that Par3L was expressed in macrophages and markedly up-regulated by oxLDL. Par3L was highly expressed in M1 macrophages at atherosclerotic lesions. In addition, knockdown of Par3L inhibited M1 macrophage polarization, and promoted M2 macrophage polarization. Thus, the central hypothesis of the proposed study is that oxLDL up-regulates Par3L to promote M1 macrophage polarization and inhibit M2 macrophage polarization, leading to As. To test this hypothesis, we plan to generate macrophage-specific Par3L knockout mice, use immunofluorescence, RNA sequencing, co-immunoprecipitation, mass spectrometry and other techniques, and analyze human atherosclerotic samples. This project is expected to reveal a novel molecular mechanism by which oxLDL promotes atherosclerosis via increasing Par3L to induce M1 macrophage polarization and inhibit M2 macrophage polarization. Successful completion of this project will provide a potential target for the intervention of As.