2011-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/648772摘要：心房顫動(atrial fibrillation)是目前最常見也是最重要的心律不整，然而其分子致病機轉並不是很清楚。最近研究指出心房在每一間隔心跳去極化或動作電位期間的交替變化(repolarization or action potential duration alternans)，會造成在空間上不同區域間不反應期不整(refractory period dispersion)，有助於傳導阻斷的發生而引發再傳入性迴路(reentry)心律不整，此現象被認為和會不會發生心房顫動有密切相關。至於心臟細胞每一間隔心跳去極化或動作電位期間交替變化的機轉，目前認為內質網鈣離子幫浦(sarcoplasmic reticulum calcium ATPase)表現減少會導致收縮期鈣離子濃度在每一間隔心跳產生交替變化(calcium transientalternans)，而此鈣離子濃度交替變化已被證實和心臟細胞動作電位期間交替變化以及心律不整發生機轉有密切關係。目前研究證實心房顫動的發生和基因或遺傳因子有密切相關。基於內質網鈣離子幫浦(sarcoplasmic reticulum calcium ATPase)表現減少和動作電位期間交替變化以及心房顫動發生的密切關係，我們假設可以決定內質網鈣離子幫浦表現高低的基因變異，可以預測病人罹患心房顫動的風險，我們將探討人類內質網鈣離子幫浦基因啟動子(promoter)區域單核酸變異和心房顫動發生的關係。本三年的研究主要利用基因定序(sequencing)來尋找內質網鈣離子幫浦基因啟動子上的單核苷酸變異(single nucleotide polymorphism)(第一年)，並利用luciferase 報告質體(reporter plasmid)及電泳位移(electrophoretic mobility shifting assay)的方法來探討單核苷酸變異會不會影響啟動子功能(第二年)，再來利用遺傳相關研究(association study)來探討具功能性之啟動子單核苷酸變異是否和臨床上心房顫動的發生有相關(第三年)，此結果將可證實以基因變異來找出心房顫動高危險群的個人化醫療概念，以提早治療及預防。<br> Abstract: Atrial fibrillation (AF) is the most common sustained and most importantarrhythmia in clinical practice. However, the detailed molecular mechanism is stillelusive. Recent studies have shown that repolarization or action potential duration(APD) alternans create dynamic spatial dispersion of repolarization. Suchrepolarization dispersion causes unidirectional block and initiation of reentranttachycardia. This repolarization-dispersion based theory has been shown to play animportant role in the initiation of AF. Regarding the mechanism of APD alternans,increasing evidence has shown that decreased sarcoplasmic reticulum calcium ATPase(SERCA) expression and function result in calcium transient alternans, whichsubsequently induces APD alternans through a sodium-calcium exchanger dependentmechanism.Recent studies have also shown that genetic factors contribute to the risk of AF.Therefore, identification of susceptibility gene(s) for AF is important for elucidatingthe detailed molecular mechanism of AF. Based on the close relationship betweenreduced SERCA expression, APD alternans and initiation of AF, we hypothesize thathuman genetic variants that determine the cardiac expression level of SERCA maydetermine an individual’s risk for AF. In the present three-year project, we plan toperform genetic association studies to test this hypothesis. In the first year, we willidentify the common polymorphisms within the promoter region of human cardiacSERCA gene. In the second year, we will clone the human cardiac SERCA genepromoter, and study the functional significance of the identified polymorphism. In thethird year, we will establish the relationship between the functional polymorphismswithin the promoter region of human cardiac SERCA gene and the risk of AF. Theresult of the present study may demonstrate that genetic polymorphism(s) can be usedas a maker to determine an individual’s risk for AF.