2013-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/655801摘要：心房顫動是目前最重要的心律，隨著人口老化，心房顫動的盛行率隨之增加，其重要性等同於心臟衰竭。心房重整是心房顫動發生和及維持重要的機制。它包含二種機制，第一種機制為結構重整（structural remodeling），指的是心房結構病變，造成各部位傳導及有效不反應期（effective refractory period）不整（heterogeneity），有助心房顫動的維持。第二種機制為電生理重整（electricalremodeling），使有效不反應期縮短，可促進心房顫動波的繼續傳導及心房內顫動波的數目變多，心房顫動因而較易維持，而有效不反應期縮短，也容易因第三期早期動作電位後去極化(late phase 3 early afterdepolarization)的現象而產生反覆期外收縮，也可使心房顫動較易反覆發作及維持，而第三期早期動作電位後去極化主要是由鈉鈣交換通道電流所形成。最近有研究顯示在心房顫動時心房的鈉鈣交換通道基因表現會增加，因此，鈉鈣交換通道的基因表現量，和一個人會不會比較容易罹患心房顫動可能有密切相關，而鈉鈣交換通道表現量，和鈉鈣交換通道基因的啟動子(promoter)活性有密切相關，因此本研究主要目的為利用基因定序(sequencing)來尋找鈉鈣交換通道基因啟動子上的單核苷酸變異(single nucleotidepolymorphism) (第一年)，並利用啟動子基因選殖及luciferase 報告質體(reporterplasmid)的方法來探討鈉鈣交換通道基因的調控以及啟動子上的單核苷酸變異會不會影響基因功能(第二年)，以及利用遺傳相關研究(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纖維顫動的發生有相關(第三年)。<br> Abstract: Atrial fibrillation (AF) is the most common sustained and important arrhythmiain clinical practice, and its incidence increases significantly with age. The mainmechanisms for the maintenance of AF are atrial remodelings. Atrial remodelingshave been classified into electrical and structural. Structural remodeling refers toprogressive architectural deterioration of atria after repeated episodes of AF. Electricalremodeling refers to shortening of action potential duration (APD) which facilitatesmulti-wavelets in AF. Shortened APD also provides the basis for the mechanism oflate phase 3 early afterdepolarization, which results in repeated prematuredepolarizations and facilitates the recurrence and maintenance of AF. Sodium-calciumexchanger (NCX) current plays the major role in late phase 3 early afterdepolarization.Recently it has been demonstrated that atrial NCX expression is increased during AF.Genetic factors may contribute to the risk of AF. Therefore, identification ofsusceptibility gene(s) for AF is important for elucidating the detailed molecularmechanism of AF. Based on the close relationship between NCX and AF, wehypothesize that human genetic variants that determine the cardiac expression level ofNCX may determine an individual’s risk for AF. In the present three-year project, weplan to test this hypothesis. In the first year, we will identify the commonpolymorphisms within the promoter region of human cardiac NCX gene. In thesecond year, we will clone the human cardiac NCX gene promoter, and study thetranscriptional regulation of NCX gene and the functional significance of theidentified NCX promoter polymorphisms. In the third year, we will establish therelationship between the functional polymorphisms and the risk of AF. The result ofthe present study may demonstrate that genetic polymorphism(s) can be used as amaker to determine an individual’s risk for AF.心房顫動 鈉鈣交換通道基因 基因的調控 單核苷酸變異atrial fibrillationsodium-calcium exchangertranscription regulationsingle nucleotide polymorphism