TRIM59抗动脉粥样硬化功能及机制的研究

Atherosclerosis is one of the major pathogens for cardiovascular diseases, such as coronary heart disease, indicating its big threat to our human health. Macrophages express scavenger receptors to bind and internalize a large amount of modified low-density lipoproteins which drives the differentiation of macrophages into lipid-laden foam cells. Therefore, the formation of foam cells is the critical step in the development of atherosclerosis. Both chronic inflammation and disorders of cholesterol metabolism have been determined to be involved the foam cell formation. TRIM59 is a member of the TRIM family, and its implication in macrophages and atherosclerosis remains unknown. The results in our preliminary studies demonstrate that TRIM59 is significantly down-regulated in activated macrophages by LPS. In contrast, high expressing TRIM59 reduces macrophage inflammatory response, promotes macrophages migration and inhibits formation of macrophage/foam cells. Moreover，the expression of TRIM59 mRNA was significantly reduced in peripheral blood mononuclear cells of patients with hyperlipidemia. These results indicate that TRIM59 may play an important role in regulation of atherosclerosis. In the current proposal, we will investigate, 1) The mechanisms of TRIM59 decreases macrophage inflammatory response; 2) If TRIM59 expression can enhance macrophage cholesterol metabolism and inhibit foam cell formation and the involved mechanisms; 3) The inhibitory effect of TRIM59 on the development of atherosclerosis in apoE deficient mice and the involved mechanisms; 4) Determination of the correlation between TRIM59 levels and atherosclerosis with clinical samples. By completing the above studies, we hope that we can identify new functions of TRIM59 in anti-atherosclerosis. We believe that our study may benefit for identification of new target for atherosclerosis treatment.

动脉粥样硬化(AS)严重危害人类健康，巨噬细胞吞噬大量脂质形成泡沫细胞是AS发生发展的关键步骤，慢性炎症与胆固醇代谢紊乱等参与此过程。TRIM59是TRIM家族成员之一，其在巨噬细胞及AS中的功能尚不明确。我们前期实验结果表明，脂多糖激活巨噬细胞并抑制TRIM59表达，反之，TRIM59降低巨噬细胞炎症反应、促进巨噬细胞迁移和抑制细胞泡沫化，同时在高血脂患者外周血单核细胞中表达量显著降低，预示TRIM59可能对AS的发生发展具有一定的调节功能。本项目我们将进一步研究：1)TRIM59降低巨噬细胞炎症反应的分子机制；2)TRIM59促进巨噬细胞胆固醇代谢、抑制巨噬细胞泡沫化功能与机制；3)体内TRIM59对apoE敲除小鼠AS发生的抑制功能及相关机制；4)收集临床样本分析TRIM59与AS的相关性。通过该研究我们将阐明TRIM59在AS发生发展中的新功能，为AS的防治提供新的思路和干预靶点。

动脉粥样硬化是一种慢性炎症性疾病，是心血管疾病发生的重要病理基础之一。由动脉粥样硬化引发的心血管疾病死亡率仍居中国居民死亡率首位，是人类健康的头号杀手之一。在动脉粥样硬化的进展过程中，巨噬细胞通过调控炎症和胆固醇代谢等参与其中。TRIM59是TRIM家族成员之一，具有E3泛素连接酶的活性，其参与许多病理过程，如炎症，细胞毒性，特别是肿瘤的发生。但是TRIM59尤其是巨噬细胞TRIM59在在动脉粥样硬化中的作用尚不明确。在本项目执行中，我们发现TRIM59在动脉粥样硬化以及非酒精性脂肪肝等疾病进展的巨噬细胞、主动脉和肝脏中表达降低；此外，我们也确定了全身敲减TRIM59能够促进体内动脉粥样硬化的发展，明确了TRIM59的抗动脉粥样硬化作用，同时在机制上我们发现：1) TRIM59敲减通过激活ERK1/2信号通路促进巨噬细胞向M1型极化，从而增加炎症因子的产生； 2) TRIM59能够通过调控PPARγ-CD36信号通路抑制巨噬细胞泡沫化以及肝脏脂质积累，从而改善脂代谢，抑制动脉粥样硬化的发展。总之，通过对本项目计划书中研究内容的完成，我们明确了TRIM59在心血管系统中的新功能，可以为临床上抗心血管疾病药物的开发提供新靶点和理论支持。

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