本文選題：STING　切入點(diǎn)：主動(dòng)脈瘤　出處：《山東大學(xué)》2017年碩士論文　論文類型：學(xué)位論文

【摘要】：研究背景:近年來,主動(dòng)脈瘤和主動(dòng)脈夾層(AAD)具有顯著的發(fā)病率和死亡率。因此對(duì)AAD的發(fā)病機(jī)制的深入理解顯得十分重要。另外,同樣重要的是需要我們盡快改善該疾病的治療方法。STING(stimulator of interferon genes)是 cGAS(cyclic GMP-AMP synthase)-STING-TBK1(TANK Binding Kinase 1)信號(hào)通路上的關(guān)鍵分子。STING能接感受來自損傷的細(xì)胞核和線粒體釋放的DNA的刺激,最終促進(jìn)炎癥的發(fā)生。最近有研究表明,STING的功能突變與血管功能損傷有關(guān)。在這篇文章,我們想驗(yàn)證我們的假設(shè):STING參與了主動(dòng)脈瘤和主動(dòng)脈夾層(AAD)的發(fā)病進(jìn)展。研究目的:研究STING在主動(dòng)脈瘤以及主動(dòng)脈夾層疾病的病理進(jìn)展機(jī)制。研究方法:我們對(duì)比了患有升主動(dòng)脈AAD病人的血管組織和正常人血管組織,通過Western Blot實(shí)驗(yàn),我們發(fā)現(xiàn)STING-TBK1信號(hào)通路被顯著激活。在培養(yǎng)的人主動(dòng)脈平滑肌細(xì)胞(SMC)里,我們來探索STING的功能。為了研究STING在小鼠AAD疾病里的作用,我們采用了高脂飲食和血管緊張素Ⅱ共同刺激來構(gòu)建的小鼠AAD模型。我們選擇野生型老鼠(WT)和STING基因敲除小鼠,通過計(jì)算AAD發(fā)病率以及測(cè)量血管直徑來比較血管損傷程度變化。另外,我們測(cè)量了血管的收縮功能,來分析STING對(duì)血管收縮功能的影響。研究結(jié)果:1、與對(duì)照組相比,在主動(dòng)脈瘤和夾層的病人血管組織中,STING-TBK1信號(hào)通路和程序性壞死信號(hào)通路(RIP3-MLKL)被顯著激活。2、在人主動(dòng)脈平滑肌細(xì)胞里,雙氧水(H2O2)和線粒體損傷能誘導(dǎo)SMC necroptosis(程序性壞死)。3、在培養(yǎng)的人平滑肌細(xì)胞里,STING-TBK1信號(hào)通路參與了雙氧水(H2O2)和CCCP誘導(dǎo)的SMC程序性壞死。4、雙氧水能誘導(dǎo)SMC線粒體損傷和線粒體DNA釋放,激活STING-TBK1信號(hào)通路。5、我們進(jìn)一步發(fā)現(xiàn),在血管緊張素和高脂飲食誘導(dǎo)的小鼠AAD模型里,STING-TBK1信號(hào)通路被激活。野生型小鼠的AAD發(fā)行率非常高。6、但是在STING基因敲除的小鼠中,SMC程序壞死以及主動(dòng)脈瘤和夾層發(fā)病率減少。7、最后,我們用TBK1抑制劑Amlexanox,抑制STING-TBK1的激活,明顯減少了野生型老鼠AAD的發(fā)病率。研究結(jié)論:STING參與了平滑肌細(xì)胞的程序性壞死過程,從而促進(jìn)主動(dòng)脈瘤和主動(dòng)脈夾層的形成,這種思路可以為主動(dòng)脈瘤和主動(dòng)脈夾層的治療提供新的思路。
[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，

本文編號(hào)：1593878