LQT3综合症病人猝死的生物钟机制--基于LQT3疾病特异性iPS细胞的疾病组织模型研究

Long-QT syndrome type 3 (LQT3) is an untreatable hereditary disorder with a high mortality rate. The etiopathogenesis of LQT3 syndrome remains unclear and remedial treatments are limited due to a lack of human cardiomyocyte (CM) sources and appropriate disease models. In this project, A cardiac tissue disease model will be created using cardiomyocytes derived from two LQT3 patient-specific induced pluripotent stem cells (iPSCs) to recapitulate LQT3-associated sudden death in vitro. Using this model, we will investigate the molecular mechanism of cardiac arrest (equivalent to sudden death in clinical) of LQT3-cardiomyocytes and elucidate its association to circadian rhythms. Also, we will perform the drug-screening study and hope to find some efficient solutions for dealing with LQT3 cardiac sudden death.

LQT3综合症是由钠通道SCN5A基因突变导致的以高猝死率为特点的先天性心脏病。由于研究材料与方法的限制，临床上对其猝死机制至今不明。依据LQT3病人猝死的表型特点与研究进展，本课题提出人LQT3疾病猝死的生物钟机制假设：认为人SCN5A基因受生物钟调控，其表达水平呈夜高昼低的震荡模式；由于LQT3患者本身受累于SCN5A基因突变导致的心肌钠通道功能异常，因而在夜间当突变基因SCN5A的表达受生物钟震荡大幅推高时，钠通道功能异常导致的心肌生理异常加剧，引发猝死。. 为了验证此假设，本课题利用两个不同LQT3综合症人类家系的疾病特异性IPS细胞在体外建立了新型LQT3心肌组织疾病模型，利用马血清激发LQT3-心肌组织细胞内生物钟震荡，通过研究LQT3-心肌组织的异常电生理行为，剖析生物钟基因与SCN5A基因节律表达的相位关系，来探讨LQT3猝死可能涉及的生物钟调控机制。

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