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）。IL-1b和GSDMDNT在乳腺癌中的确切作用 心肌细胞和心房肌细胞发生在很大程度上是未知的。我们的初步数据显示， 心肌细胞特异性敲低IL-1b受体1（IL-1 R1）可降低AF小鼠的易感性， 心肌细胞NLRP 3功能获得。同时，GSDMDNT在小鼠心房特异性过表达， （aGSDMDNT）也产生用于AF发展的药物底物。因为GSDMDNT的主要功能 是形成质膜孔，允许细胞释放IL-1b，并且IL-1b蛋白在 在aGSDMDNT小鼠中，我们假设GSDMDNT/IL-1b关系通过促进AF的发生而产生AF的底物。 NLRP 3-炎性小体激活的前馈环。使用小鼠和人类心房系统，我们提出1） 阐明IL-1b信号转导在心肌细胞和心房颤动发生中的作用，2）确定 心肌细胞GSDMDNT在心房颤动发生中的作用和功能，3）建立并验证 GSDMDNT/IL-1b关系作为心房肌中NLRP 3-炎性小体激活的前馈环的驱动因素 胚胎发生这些研究的结果将为心房特异性靶向IL-10提供概念验证。 房颤患者IL-1b信号通路，揭示IL-1b和GSDMDNT在心房肌细胞中的新的独特功能。 心肌细胞及其对AF发展的具体贡献。

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). The precise functions of IL-1b and GSDMDNT in cardiomyocytes and atrial arrhythmogenesis are largely unknown. Our preliminary data revealed that cardiomyocyte-specific knockdown of IL-1b receptor type-1 (IL-1R1) attenuates susceptibility to AF of mice with cardiomyocyte NLRP3 gain-of-function. Meanwhile, atrial specific overexpression of GSDMDNT in mice (aGSDMDNT) also creates an arrhythmic substrate for AF development. Because the main function of GSDMDNT is to form plasma membrane pores allowing the cell release of IL-1b and IL-1b protein is upregulated in aGSDMDNT mice, we hypothesized that this GSDMDNT/IL-1b nexus creates a substrate for AF by promoting a feedforward loop of NLRP3-inflammasome activation. Using mouse and human atrial systems we propose to 1) elucidate the role of IL-1b signaling in cardiomyocytes and atrial arrhythmogenesis, 2) establish the causative role and the functions of cardiomyocyte GSDMDNT in atrial arrhythmogenesis, and 3) establish and validate GSDMDNT/IL-1b nexus as the driver of a feedforward loop of NLRP3-inflammasome activation in atrial arrhythmogenesis. The outcome of these studies will provide a proof-of-concept for atrial specific targeting of IL- 1b signaling in AF patients and uncover novel and unique functions of IL-1b and GSDMDNT in atrial cardiomyocytes and their specific contributions to AF development.