Characterization of SHOX2 and SHOX2 target genes in the pathogenesis of cardiac arrhythmias

心律失常发病机制中SHOX2及其靶基因的特征为了阐明窦房结发育的分子机制以及心律失常的病理生理过程，我们将讨论起搏器特异性表达的基因SHOX2，其靶基因和SHOX2相关分子的关键作用。利用Shox2作为分子工具，我们成功地建立了一个基于胚胎干细胞的模型系统，该模型系统将用于研究调控早期起搏器分化的新分子途径。此外，我们将详细分析最近发现的SHOX 2突变和SHOX 2 3 UTR（非翻译区）变异在房颤患者中的功能相关性。我们将使用基于细胞培养的体外方法，以及斑马鱼作为体内模型系统。此外，我们将在更多的窦房结功能障碍患者中进行SHOX2基因突变筛查。为了在功能上表征SHOX2编码变体和3 UTR变体，其产生新的microRNA结合位点，我们将利用诱导多能干细胞（iPSC）建立患者特异性疾病模型。

Characterization of SHOX2 and SHOX2 target genes in the pathogenesis of cardiac arrhythmia. To elucidate molecular mechanisms underlying sinoatrial node development as well as pathophysiological processes of cardiac arrhythmias, we will address the critical role of the pacemaker-specific expressed gene SHOX2, its target genes and SHOX2 associated molecules. Using Shox2 as a molecular tool, we successfully established an embryonic stem cell based model system, which will be used to investigate novel molecular pathways regulating early pacemaker differentiation. Furthermore, we will analyze the functional relevance of recently identified SHOX2 mutations and a SHOX2 3 UTR (untranslated region) variant in patients with atrial fibrillation in detail. We will use cell culture based in vitro approaches, as well as Zebrafish as an in vivo model system. In addition, we will perform mutational screening of the SHOX2 gene in further patients with sinusnode dysfunction. To functionally characterize the SHOX2 coding variants and the 3 UTR variant, which creates novel microRNA binding sites, we will utilize induced pluripotent stem cells (iPSCs) to establish a patient-specific disease model.