The Role of Gasdermin-D/Interleukin-1 Nexus in Atrial Arrhythmogenesis

项目摘要 心房颤动（AF）是最常见的心律失常。增强的NACHT、LRR和PYD结构域的活化- 含有蛋白3'（NLRP 3）的炎性体在促进相关的促炎事件中起因果作用。 AF的发展。NLRP 3炎性体的激活产生两种主要效应物：白细胞介素（IL）-1b和 裂解的（活性）N-末端gasdermin-D（GSDMDNT）。父母补助金的结果表明，GSDMD可以 通过先前未被认识到的不依赖于心房颤动的替代功能促进心房颤动发生， 心肌细胞和膜修复机制通过ESCRT III可以防止过度的细胞死亡， AF发展过程中炎性小体激活。在本申请中，我们将阐明 GSDMDNT和心肌细胞中ESCRT III介导的膜修复机制的参与。

PROJECT SUMMARY Atrial fibrillation (AF) is the most frequent arrhythmia. Enhanced activation of ‘NACHT, LRR and PYD domains- containing protein 3’ (NLRP3) inflammasome plays a causal role in promoting proarrhythmic events associated with AF development. Activation of NLRP3 inflammasome produces two major effectors: interleukin (IL)-1b and cleaved (active) N-terminal gasdermin-D (GSDMDNT). Results from parent grant suggest that that GSDMD could promote atrial arrhythmogenesis by previously unrecognized pyroptosis-independent alternative functions in cardiomyocytes and the membrane-repair machinery via ESCRT III may prevent excessive cell death upon inflammasome activation during AF development. In this application, we will elucidate the alternative function of GSDMDNT and the involvement of ESCRT III-mediated membrane repair machinery in cardiomyocytes.