STING对主动脉瘤及主动脉夹层的影响及机制研究

发布时间：2018-03-10 15:10

  本文选题：STING　切入点：主动脉瘤　出处：《山东大学》2017年硕士论文　论文类型：学位论文

【摘要】：研究背景:近年来,主动脉瘤和主动脉夹层(AAD)具有显著的发病率和死亡率。因此对AAD的发病机制的深入理解显得十分重要。另外,同样重要的是需要我们尽快改善该疾病的治疗方法。STING(stimulator of interferon genes)是 cGAS(cyclic GMP-AMP synthase)-STING-TBK1(TANK Binding Kinase 1)信号通路上的关键分子。STING能接感受来自损伤的细胞核和线粒体释放的DNA的刺激,最终促进炎症的发生。最近有研究表明,STING的功能突变与血管功能损伤有关。在这篇文章,我们想验证我们的假设:STING参与了主动脉瘤和主动脉夹层(AAD)的发病进展。研究目的:研究STING在主动脉瘤以及主动脉夹层疾病的病理进展机制。研究方法:我们对比了患有升主动脉AAD病人的血管组织和正常人血管组织,通过Western Blot实验,我们发现STING-TBK1信号通路被显著激活。在培养的人主动脉平滑肌细胞(SMC)里,我们来探索STING的功能。为了研究STING在小鼠AAD疾病里的作用,我们采用了高脂饮食和血管紧张素Ⅱ共同刺激来构建的小鼠AAD模型。我们选择野生型老鼠(WT)和STING基因敲除小鼠,通过计算AAD发病率以及测量血管直径来比较血管损伤程度变化。另外,我们测量了血管的收缩功能,来分析STING对血管收缩功能的影响。研究结果:1、与对照组相比,在主动脉瘤和夹层的病人血管组织中,STING-TBK1信号通路和程序性坏死信号通路(RIP3-MLKL)被显著激活。2、在人主动脉平滑肌细胞里,双氧水(H2O2)和线粒体损伤能诱导SMC necroptosis(程序性坏死)。3、在培养的人平滑肌细胞里,STING-TBK1信号通路参与了双氧水(H2O2)和CCCP诱导的SMC程序性坏死。4、双氧水能诱导SMC线粒体损伤和线粒体DNA释放,激活STING-TBK1信号通路。5、我们进一步发现,在血管紧张素和高脂饮食诱导的小鼠AAD模型里,STING-TBK1信号通路被激活。野生型小鼠的AAD发行率非常高。6、但是在STING基因敲除的小鼠中,SMC程序坏死以及主动脉瘤和夹层发病率减少。7、最后,我们用TBK1抑制剂Amlexanox,抑制STING-TBK1的激活,明显减少了野生型老鼠AAD的发病率。研究结论:STING参与了平滑肌细胞的程序性坏死过程,从而促进主动脉瘤和主动脉夹层的形成,这种思路可以为主动脉瘤和主动脉夹层的治疗提供新的思路。
[Abstract]:Background: in recent years, AAD (aortic aneurysm and aortic dissection) has a significant morbidity and mortality. Therefore, it is important to understand the pathogenesis of AAD. Equally important is that we need to improve the treatment of the disease as soon as possible. STINGstimulator of interferon genes1 is a key molecule in the cGAS(cyclic GMP-AMP synthase)-STING-TBK1(TANK Binding Kinase 1 signaling pathway that can sense the stimulation of DNA from damaged nuclei and mitochondria. Finally, it promotes inflammation. Recent studies have shown that the functional mutation of stinging is associated with vascular dysfunction. We want to verify our hypothesis that STING is involved in the pathogenesis of aortic aneurysms and aortic dissection. Objective: to study the pathological progression of STING in aortic aneurysms and aortic dissection. Vascular tissue in patients with ascending aortic AAD and normal vascular tissue, In the Western Blot experiment, we found that the STING-TBK1 signaling pathway was significantly activated. In cultured human aortic smooth muscle cells (SMC), we explored the function of STING. We used a high-fat diet and angiotensin 鈪，

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