膜联蛋白A1影响动脉粥样硬化斑块的形成和稳定性

We have previously found that high-density lipoprotein (HDL) play an important protective role in endothelial cells. We published an article this year, and confirmed HDL can promote the expression of annexin A1 (ANXA1) on endothelial cells, which has anti-inflammatory effects. This function cannot do without HDL receptor, SR-B1. The results of our pilot study also found that modified HDL occurs in diseases including diabetes can down-regulate the expression of ANXA1. Latest research on ANXA1 has focused on inflammatory cells, and we will focus in endothelial cell and smooth muscle cell. We hypothesized that in atherosclerosis formation and stabilization process, ANXA1 may play an important role in vascular endothelial and smooth muscle cells . We will combine carotid artery plaque mouse model and endothelium or smooth muscle cell specific ANXA1 knockout mice to study ANXA1's role in plaque formation and stability. We will specifically knockout endothelium's SR- BI to further investigate whether endothelial cells' SR-BI is involved in this function. We will also explore the relationship between ANXA1 expression and vascular endothelial or smooth muscle cell proliferation and migration, as well as inflammatory cytokines released. We will also use our method published in Nanoscale using magnetic nanoparticle drug technology to release ANXA1 & HDL mimetic peptides around the plaques to further study the relationship between the formation and stability of plaque and ANXA1.

我们前期发现高密度脂蛋白(HDL)对内皮细胞起重要保护作用，今年我们的文章进一步证实HDL能够促内皮细胞中膜联蛋白（ANXA1）的表达从而发挥抗炎作用，而这又离不开HDL受体SR-BI.我们预实验结果也发现HDL在疾病状态的修饰会使ANXA1的表达下调。ANXA1过去的研究都集中在炎症细胞，我们推测在动脉粥样硬化形成与稳定过程中，血管内皮和平滑肌细胞表达的ANXA1可能发挥重要功能。我们将结合全身以及内皮或平滑肌特异敲除的ANXA1小鼠与颈部动脉套管法来研究ANXA1在其中的重要作用，我们也将通过内皮特异敲除SR-BI小鼠来研究内皮细胞中SR-BI是否参与这一功能。我们还将通过细胞实验探索ANXA1的表达与血管内皮和平滑肌细胞增殖与迁移的关系以及与炎症因子释放的关系。我们还将用我们发表在Nanoscale上的生物工程技术将模拟肽定点释放，通过干预的方法研究ANXA1对斑块形成和稳定的影响。

高密度脂蛋白（HDL）在过去的几十年中都被认为是与心血管疾病呈反相关的因素，但其在生理以及病生理中的作用还不够明确，特别是很多临床药物在提高HDL的临床试验都失败。我们发现膜联蛋白A1（ANXA1）可以抑制动脉粥样硬化斑块的形成，抑制动脉瘤与动脉夹层等疾病的进展。HDL是脂代谢领域中发挥重要作用的关键一环，在HDL研究的引导下，我们在脂代谢领域取得了一系列值得关注的研究成果。我们发现肠道菌群代谢物，如氧化三甲胺（TMAO）等可以促进小鼠细胞衰老、加剧认知障碍等。在不同的环境下，HDL功能也会发生改变，我们发现在较高污染条件下人类的HDL功能会发生功能性障碍，可能引起全身性炎症和氧化应激。相应结果发表SCI论文15篇。