血管内皮衰老引起血管壁炎症紊乱和重构的机制研究

Senescence-associated secretory phenotype (SASP) is a critical factor in vascular endothelial senescence, vascular aging, vascular inflammation and vascular remodeling. However, the role of endothelial SASP and its regulatory mechanisms remain to be explored. Our previous data indicate that the knockout of TRX2 leads to mitochondrial dysfunction, endothelial cell senescence, activation of NF-κB and SASP production; Therefore, we hypothesize that mitochondrial homeostasis maintained by TRX2 is an essential mechanism to protect vascular endothelium from aging, SASP and vascular remodeling, and the regulation of vascular senescence and SASP by TRX2 may be achieved by modulating the activity of NF-κB. In this project, we will further testify our hypothesis at the level of cell-cell interaction, and cell-tissue interaction by using the transgenic mice, knockout mice and cell culture models, combining with proteomics and transcriptomics analyses as well as the approaches of molecular and cellular biology. We anticipate that our project will dissect the role and the regulation mechanism of SASP during endothelial senescence and pathological changes associated with vascular remodeling and aging.

衰老相关的分泌表型(SASP)是内皮衰老、血管衰老、炎症及重构的重要影响因素，但其作用与调控机制有待探讨。前期研究发现，TRX2敲除导致线粒体功能失衡、内皮细胞衰老、激活NF-κB并促进SASP产生；衰老内皮细胞TRX2表达明显降低据此，我们假设：TRX2对线粒体稳态的维持作用是保护血管内皮免于衰老、SASP及血管重构的重要机制，TRX2对血管衰老与SASP的调控作用可能通过影响NF-κB的活性来实现，TRX2的加工处理可受SENP1调控作用所控制。本课题将利用转基因小鼠、基因敲除小鼠、细胞模型及组学分析，在分子、细胞、细胞-细胞、细胞-基质等层次对这一假说进行验证。预期将为解析内皮细胞衰老过程中SASP的调控机制，为阐释SASP对血管重构以及衰老相关血管生理病理改变的影响与机制提供实验依据。

衰老相关的分泌表型(SASP)是内皮衰老、血管衰老、炎症及重构的重要影响因素，但其作用与调控机制有待探讨。前期研究发现，TRX2敲除导致线粒体功能失衡、内皮细胞衰老、激活NF-κB并促进SASP产生；衰老内皮细胞TRX2表达明显降低；沉默HuR可降低TRX2表达；HuR缺失导致IL-1、IL-6及TGF-β表达升高。生物信息学分析发现少量miRNA和LncRNA可能参与TRX2的调控。进一步的机制研究证实，miR-15a家族抑制TRX2的表达，XIST作为竞争性内源性RNA控制miR-15a家族/TRX2轴的表达，从而导致线粒体功能障碍。后续筛选发现lncRNA-XIST/miR-15a家族调控一系列线粒体相关蛋白，从而发挥抗氧化作用。因此我们得出结论：TRX2对线粒体稳态的维持作用是保护血管内皮免于衰老、SASP及血管重构的重要机制，TRX2对血管衰老与SASP的调控作用是受miR-15a家族的调控作用所控制。本研究为解析内皮细胞衰老过程中SASP的调控机制，为阐释SASP对血管重构以及衰老相关血管生理病理改变的影响与机制提供实验依据。