A (patho)physiological study of CVB3 infection and HCN4 in a human iPSC-based pacemaker system

将人类体细胞重新编程为多能性的技术使得几乎可以无限制地获得人类诱导多能干细胞（hiPSC）。在基础实验心脏病学中，hiPSC转分化细胞提供亚型特异性心肌细胞，允许研究（病理）生理细胞功能。拟议的工作计划旨在建立对正常和受疾病影响的人体起搏器系统的全面机械理解。将建立改进的iPSC起搏器系统。将详细评估通过新方法产生的iPSC起搏细胞，并与来自人类窦房结的细胞进行比较。在这些细胞中，将研究引起科萨基病毒B3表达的心肌病对电节律性和细胞结构的影响。此外，将分析临床相关的HCN 4突变HCN 4-G482 R对电节律性和细胞结构的影响。HCN 4-G482 R的具体生物物理特征也将进行更详细的研究。我们预计，新的iPSC系统将允许病毒性心肌炎和通道病的新见解。

The technology to reprogram human somatic cells back to pluripotency enables virtually unlimited access to human induced pluripotent stem cells (hiPSC). In basic experimental cardiology, hiPSC-transdifferentiated cells provide subtype-specific cardiomyocytes allowing for studies of (patho)physiological cellular functionalities. The proposed work plan aims at establishing a comprehensive mechanistic understanding of the normal and disease-impacted human pacemaker system. An improved iPSC pacemaker system will be established. iPSC pacemaker cells generated by a novel methodology will be evaluated in detail and compared with cells from the human sinus node. In these cells, the impact of cardiomyopathy causing Coxsackie virus B3 expression on electrical rhythmicity and cell structure will be studied. Further, the impact of the clinically relevant HCN4 mutation HCN4-G482R on electrical rhythmicity and cell structure will be analysed. Specific biophysical features of HCN4-G482R will also be studied in more detail. We expect that the novel iPSC-System will allow for new insights of viral myocarditis and a channelopathy.