本文選題：KCNQ1 + 房室傳導阻滯　； 參考：《同濟大學》2006年碩士論文

【摘要】： 背景房室傳導阻滯可見于部分心房顫動患者，然而其分子機制并不清楚。三年前陳等報道KCNQ1基因S140G突變可以引起家族性心房顫動，同時通過動態(tài)心電圖檢查發(fā)現(xiàn)這個家系中大部分心房顫動患者合并房室傳導阻滯，KCNQ1 S140G突變與房室傳導阻滯共分離。因此我們推測房室傳導阻滯與心房顫動可能有相同的分子變異基礎。 目的建立轉KCNQ1 S140G突變體小鼠模型，進一步明確KCNQ1 S140G突變體致心房顫動和或致房室傳導阻滯的病理生理作用。 方法提取正常人的心肌組織RNA，，逆轉錄得到cDNA，亞克隆入心肌特異性表達載體，定點誘變得到KCNQ1 S140G，經(jīng)測序證實無誤后線性化借助顯微注射裝置將其注射入受精卵，移入代孕小鼠輸卵管，進行繁殖而建立人S140G突變型KCNQ1心肌特異性表達轉基因小鼠模型，對該模型進行遺傳學檢測、表達分析和表型檢測。 結果我們成功建立了人S140G突變型KCNQ1轉基因小鼠模型，四品系轉基因模式小鼠的心臟中均高度表達KCNQ1 S140G突變體，對照組未見突變表達。小鼠體表心電圖檢測發(fā)現(xiàn)65％陽性小鼠有一度、二度、高度和三度房室傳導阻滯事件，但未見心房顫動表型，而未含有該突變的對照小鼠既未發(fā)現(xiàn)房室傳導阻滯也未見心房顫動事件。 結論1．S140G突變型KCNQ1心肌特異性過表達可以引起小鼠房室傳導阻滯，但是不能復制出心房顫動表型；2．KCNQ1的分子缺陷不但與人類心房顫動有關，而且還可引起人類和小鼠房室傳導阻滯；3．S140G突變型KCNQ1轉基因小鼠模型可能是探索房室傳導阻滯病理生理機制和藥物干預的良好工具。
[Abstract]:Background atrioventricular block is seen in some patients with atrial fibrillation, but its molecular mechanism is unclear. Chen et al reported three years ago that S140G mutation of KCNQ1 gene could cause familial atrial fibrillation. At the same time, it was found that KCNQ1 S140G mutation was separated from atrioventricular block in most patients with atrial fibrillation in this pedigree by dynamic electrocardiogram. Therefore, we speculate that atrioventricular block and atrial fibrillation may have the same molecular basis of variation. Objective to establish a mouse model of KCNQ1 S140G mutant and to further clarify the pathophysiological effects of KCNQ1 S140G mutant on atrial fibrillation and atrioventricular block. Methods normal human myocardial RNAs were extracted, cDNA was obtained by reverse transcription and subcloned into myocardial specific expression vector. KCNQ1 S140G was obtained by site-directed mutagenesis. After sequencing, it was linearized and injected into fertilized eggs by microinjection device. The transgenic mouse model of specific expression of human S140G mutant KCNQ1 was established by transferring into the fallopian tube of surrogate mice. The genetic analysis, expression analysis and phenotypic detection of the model were carried out. Results the human S140G mutant KCNQ1 transgenic mouse model was successfully established. KCNQ1 S140G mutant was highly expressed in the heart of the four strain transgenic mice, but no mutation was found in the control group. Body surface electrocardiogram showed that 65% of the positive mice had once, second, high and third degree atrioventricular block events, but no phenotype of atrial fibrillation. Neither atrioventricular block nor atrial fibrillation was found in the control mice without the mutation. Conclusion 1.Myocardial specific overexpression of S140G mutant KCNQ1 can induce atrioventricular block in mice, but it can not replicate the phenotype of atrial fibrillation. 2. The molecular defect of KCNQ1 is not only related to human atrial fibrillation. Moreover, the transgenic mouse model of KCNQ1 mutant 3.S140G may be a good tool to explore the pathophysiological mechanism of atrioventricular block and drug intervention.
【學位授予單位】：同濟大學
【學位級別】：碩士
【學位授予年份】：2006
【分類號】：R-332;R541.7

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