致心率失常性心肌病(ARVD)是致心脏猝死的高风险显性遗传病，具有炎症活性增强、心脏纤维化等症状。在严重的高死亡率、完全外显的ARVD亚型ARVD5的多个病人家族中，已经鉴定出了同样的TMEM43-S358L突变。NF-kB信号在炎症反应中起基础性作用。通过生物分子荧光互补筛选，我们鉴定出TMEM43是NF-kB信号激活的关键元件。在心肌细胞中TMEM43-S358L突变增强GPCR介导的NF-kB信号和心脏纤维化基因表达。因此，我们假设：TMEM43-S358L突变通过激活NF-kB信号引起炎症反应从而导致ARVD的病理发生。本项目将应用TMEM43-S358L、IKKβ心脏特异性敲除和血管紧张素2灌流等小鼠模型来研究TMEM43-S358L突变及其诱导的NF-kB炎症反应对ARVD病理的贡献。该研究将建立炎症反应与ARVD心肌病之间的有机联系，为该疾病进行抗炎症治疗和新药开发提供基础。

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVD) is a genetic disorder that leads to high risk of sudden cardiac death. The hearts of ARVD patients have severe symptoms like increasing inflammation responses, cardiac fibrosis and enlarged cardiac chambers. Previous studies have identified TMEM43-Ser358Leu mutation as the cause of ARVD5, a severe ARVD subtype with high lethality and fully penetrance found in various patient families in different countries. NF-kB is a family of transcription factors, which plays essential roles in inflammation, and is activated in various human chronic inflammatory diseases. Using a Bimolecular Fluorescence Complementation (BiFC)-based functional genomics screening, we identified TMEM43 as a key component in GPCR-induced NF-kB activation. We found that TMEM43-S358L mutant enhanced GPCR-induced NF-kB activation and the expression of cardiac fibrosis genes. Therefore, we propose that TMEM43 S358L mutation activates NF-kB signaling and inflammation, thereby contributes to ARVD pathogenesis. We have generated a TMEM43-S358L knock-in mouse strain, and established Angiotensin II infusion mouse model to investigate the contributions of TMEM43-S358L to ARVD pathogenesis, and apply NF-kB-GFP transgenic mouse，IKK beta-cardiac specific knockout mouse for NF-kB signaling deficiency to study the roles of NF-kB inflammation signaling in ARVD. Our study will provide the genetic evidence linking chronic inflammation to ARVD cardiomyopathy, and provide the molecular insight for designing anti-inflammation therapeutic agents for treatment of ARVD patients.