本文選題：右室心尖起搏　切入點：基因芯片　出處：《南京醫(yī)科大學》2016年博士論文

【摘要】：背景心臟起搏器植入是治療緩慢性心律失常唯一有效的治療措施。右室心尖(right ventricular apex,RVA)起搏是目前臨床廣泛應(yīng)用的起搏方式。右室心尖起搏可導致心肌細胞電重構(gòu)、組織學重構(gòu),房顫的發(fā)生率增加,最終可能導致心力衰竭。有研究報道心功能正常的患者RVA起搏對心室結(jié)構(gòu)及功能的影響較小。RVA起搏術(shù)后在心室結(jié)構(gòu)及功能均正常的階段,分子生物學層面是否已經(jīng)發(fā)生改變,目前研究較少。線粒體與心血管疾病的有關(guān)研究日益增多。線粒體融合蛋白視神經(jīng)萎縮蛋白1(opticatrophy 1,OPA1)參與心力衰竭的發(fā)生發(fā)展。RVA起搏術(shù)后OPA1的外周血表達水平改變及其具體的生物學作用及相關(guān)調(diào)控機制,還需要進一步深入研究。目的對心功能正常患者RVA起搏術(shù)后外周血全基因進行檢測,并篩選基因標志物,探討其生物學作用。方法利用外周血表達譜基因芯片檢測方法,測定10例患者RVA起搏術(shù)前和術(shù)后一周外周血全基因表達水平,另外有3例患者只測定了術(shù)前外周血全基因表達水平。Transcriptome Analysis Console 3.0 軟件采用ANOVA 算法,計算P0.05 時的差異表達基因,通過DAVID(the Database for Annotation,Visualization and Integration Discovery)在線數(shù)據(jù)庫對差異表達≥2倍的基因進行生物信息學分析。應(yīng)用蒙特卡洛、邏輯回歸進行分析運算,篩選出對起搏器植入前后樣本有最佳甄別作用的基因組合。結(jié)果外周血表達譜基因芯片研究結(jié)果顯示RVA起搏術(shù)后一周與術(shù)前比較存在大量差異表達基因,顯著上調(diào)基因有228個,顯著下調(diào)的基因有281個。差異表達的基因全部作用于細胞連接、細胞膜和糖蛋白,主要參與離子跨膜轉(zhuǎn)運、細胞運動性、突觸前膜聚集等生物過程。差異表達的基因參與鈣離子信號通路、調(diào)節(jié)糖鞘脂的生物合成、神經(jīng)活性受體與配體相互作用3條信號通路。其中鈣離子調(diào)節(jié)信號通路發(fā)生差異表達的基因數(shù)目最多,包括CaMKⅡ2A、RYR2、IP3R。本研究基于外周血表達譜基因芯片研究的結(jié)果,根據(jù)邏輯回歸分析方法,篩選出對起搏器植入前后樣本有最佳甄別作用的基因組合(OPA1、NDUFA1、PRDX1、CTSA、STK10),敏感性91%,特異性92%,準確性91.3%。在起搏器植入術(shù)后患者與健康對照組的差異基因表達分析中,ROC曲線分析顯示該基因組合的曲線下面積值(area under curve,AUC)0.90(95%CI 0.80-0.97,P0.001)�；�因組合中除了 STK10,其余都與線粒體相關(guān),其中OPA1與心血管疾病關(guān)系密切。結(jié)論心功能正常患者RVA起搏術(shù)后一周與術(shù)前術(shù)前比較存在大量差異表達基因,篩選出對起搏器植入前后有最佳甄別作用的基因組合,對差異表達基因進行生物信息學分析,為進一步的qRT-PCR驗證奠定了一定基礎(chǔ)。
[Abstract]:Background cardiac pacemaker implantation is the only effective treatment of slow arrhythmia treatment. Right ventricular apex (right ventricular, apex, RVA) is a widely used clinical pacing. The pacing right ventricular apical pacing can lead to myocardial cell electrical remodeling, tissue remodeling, increased incidence of atrial fibrillation, may ultimately lead to heart failure. Research reports normal cardiac function in patients with RVA pacing on ventricular structure and function after.RVA pacing in small ventricular structure and function were normal, whether the molecular level has changed, there is less research on the related research. More mitochondria and cardiovascular disease increased. Mitochondrial fusion protein of optic nerve atrophy protein 1 (opticatrophy 1 OPA1), changes in the expression of OPA1 in peripheral blood of the occurrence and development of.RVA pacing in heart failure and biological effects of specific and related The regulation mechanism, we still need further study. The purpose of normal cardiac function in patients with RVA pacing after peripheral blood gene detection and screening of genetic markers, study its biological effect. Methods the gene chip detection method using peripheral blood, 10 cases of patients with RVA pacing before and after surgery in a week the whole blood gene expression levels were measured in 3 cases only by preoperative peripheral blood gene expression level of.Transcriptome Analysis Console 3 software using ANOVA algorithm, calculate the differences between P0.05 gene expression by DAVID (the Database, for Annotation, Visualization and Integration Discovery) bioinformatics analysis of differentially expressed online database more than 2 times of the gene. The application of Monte Carlo, logistic regression analysis calculation, screened the best screening of samples before and after pacemaker implantation for combination. The results of peripheral blood gene expression microarray results showed that RVA pacing one week after operation compared with the preoperative, there are a large number of differentially expressed genes, 228 genes were up-regulated and 281 genes were down regulated significantly. The differentially expressed genes in the role of all cell junctions, cell membrane and egg white sugar, mainly involved in the transmembrane ion transport, cell motility, presynaptic membrane aggregation and other biological processes. The differential expression of genes involved in calcium signaling pathway, glycosphingolipid biosynthesis regulation, neural activity and receptor ligand interaction 3 pathways. The number of genes in which the calcium ion regulation signal pathway differentially expressed most, including CaMK II 2A, RYR2, IP3R. based on the study of peripheral blood gene expression microarray results, according to the logistic regression analysis method, screening the best combination of gene screening role of samples before and after pacemaker implantation (OPA1, NDUFA1, PR DX1, CTSA, STK10), the sensitivity was 91%, specificity 92%, accuracy analysis of differential gene expression in 91.3%. after pacemaker implantation in patients with healthy control group, ROC curve analysis showed that the gene combination area under the curve value (area under curve, AUC) 0.90 (95%CI 0.80-0.97, P0.001). In addition to the combination of genes STK10, the rest are related with mitochondria, the relationship between OPA1 and cardiovascular disease closely. Conclusion cardiac function in patients with normal RVA pacing a week after surgery and preoperative before the existence of a large number of differentially expressed genes, screening the best combination of gene screening role of pacemaker implantation after expression, bioinformatics analysis of gene differences. Lays the foundation for further verification of qRT-PCR.

【學位授予單位】：南京醫(yī)科大學
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R541.7

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