心脏特异性转录因子基因调控区域与先天性心脏病的分子遗传学研究

随着外科有效治疗的开展，先天性心脏病（先心病）病人存活时间延长，成人先心病群体不断扩大。术后成人先心病病人于中年期出现心脏并发症，如心衰、心律不齐和猝死等，其死亡率显著高于正常人群，近来认为与其遗传缺陷有关。迄今为止，大多数先心病的遗传学病因尚不清楚。目前分子遗传学研究主要集中分析基因的编码区域及拼接位点。研究显示，心脏特异性转录因子呈现明显的基因剂量效应。我们假设认为，心脏特异性转录因子基因表达水平的改变可能是先心病的重要原因。在本课题中，我们采用候选基因和病例-对照策略，对心脏特异性转录因子基因（GATA4、NKX2-5、TBX1、TBX5和TBX20）的调控区域，即启动子和增强子等，进行分子遗传学分析，首先发现先心病相关的DNA序列变异（DSVs），在体外和体内进行生物学功能分析，并探讨DSVs发挥作用的分子机制。因此，本课题将为干预和治疗成人先心病的心脏心并发症提供基础和依据。

Due to successful surgical treatment, patients with congenital heart disease (CHD) live longer and population of adult CHD patients is keeping growing. At middle age, adult CHD patents with surgical cardiac correction suffer from cardiac complications, such as heart failure, arrhythmia and sudden death. Mortality of adult CHD patients is significantly higher than general population, which is probably caused by the genetic defects. To date, genetic causes for CHD remain largely unknown.Currently, genetic studies have been focused on finding mutations within coding regions and splicing sites. As cardiac-specific transcription factors act as dosage-sensitive regulators in the heart development,we hypothesized that altered levels of cardiac-specific transcription factor genes, caused by DNA sequence variants (DSVs) with the regulatory regions, are important causes of CHD.In this study, candidate gene and case-control strategies are employed to analyze the regulatory regions (promoters and enhancers) of cardiac transcription factor genes (GATA4, NKX2-5, TBX1, TBX5 and TBX20). We will first identity DSVs in diverse types of CHD patients, then analyze the transcriptional activities in cultured cells and experimental model animal. Furthermore, molecular mechanisms on how DSVs affect transcriptional activities of the regulatory regions will be explored and elucidated. Thus, the study will provided insights into designing novel ways for intervention and treatment of cardiac complications in adult CHD patients.