Defining novel mechanisms of sudden death in Dravet syndrome: Dysregulation of sodium channels in the heart

项目摘要 癫痫猝死(SUDEP)是一种致命的并发症，发生在癫痫患者中，谁 在其他方面都很健康。德拉韦综合征(DS)，由钠通道(NAV)功能丧失引起 等位基因Nav1.1与SUDEP的风险特别高相关。值得注意的是，SUDEP的意外死亡 反映了心脏性猝死(SCD)--由心律失常引起的意外死亡。新兴 有证据表明，大脑和心脏之间存在生理上的共性，这表明 癫痫疾病背后的分子机制也可能直接影响心脏，导致生命- 有危险的心律失常，从而导致心源性心脏病。然而，DS直接 影响心脏，促进心律失常和SCD尚不清楚。因此，我们建议利用模型 以解决这一认识上的差距，并探讨直接心脏重塑在SCD中的作用。使用这些 模型，我们将检验这样一种假设，即导致遗传性癫痫障碍的NAM缺陷，如DraveT 综合征，心脏钠/钙循环失调，从而促进危及生命的心律失常 致SCD。因此，我们建议：1)定义组织特异性表达的表型和结构影响 DS相关缺陷。2)确定DS相关的Na+/Ca~(2+)信号纳域的功能影响 重构对心肌钙离子处理的影响。3)评价靶向Na+/Ca~(2+)信号纳米域治疗SCD的疗效 预防。从这些研究中收集的信息将被用于开发新的治疗方法 DS中的SCD。

Project Summary Sudden, unexpected death in epilepsy (SUDEP) is a fatal complication, occurring in patients with epilepsy, who were otherwise healthy. Dravet syndrome (DS), which results from a loss of function of the sodium channel (NaV) isoform NaV1.1, is associated with a particularly high risk of SUDEP. Notably, the unexpected mortality of SUDEP mirrors cases of sudden cardiac death (SCD) – unexpected death resulting from cardiac arrhythmias. Emerging evidence points to physiological commonalities between the brain and the heart, suggesting that the very molecular mechanisms that underlie epileptic disorders could also directly impact the heart, leading to life- threatening cardiac arrhythmias and thereby, SCD. However, the precise mechanisms by which DS directly impact the heart to promote cardiac arrhythmias and SCD remain unknown. Thus, we propose to utilize models of DS to address this gap in knowledge and to explore the role of direct cardiac remodeling in SCD. Using these models, we will test the hypothesis that defects in NaVs that underlie inherited epileptic disorders, such as Dravet syndrome, dysregulate cardiac Na+/Ca2+ cycling, thereby promoting life-threatening arrhythmias and contributing to SCD. Thus, we propose to: 1) Define the phenotypic and structural impacts of tissue-specific expression of DS-associated defects. 2) Determine the functional impact of DS-associated Na+/Ca2+ signaling nanodomain remodeling on cardiac Ca2+ handling. 3) Assess efficacy of targeting Na+/Ca2+ signaling nanodomains for SCD prevention. Information gleaned from these studies will be used to develop new therapeutic approaches to treat SCD in DS.