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， 其他方面都很健康Dravet综合征（DS），由钠通道（NaV）功能丧失引起 亚型NaV1.1与SUDEP的特别高风险相关。值得注意的是，SUDEP的意外死亡 反映了心源性猝死（SCD）的病例-心律失常导致的意外死亡。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， 癫痫疾病的分子机制也可能直接影响心脏，导致生命- 威胁心律失常从而导致SCD。然而，DS直接 影响心脏以促进心律失常和SCD仍然未知。因此，我们建议利用模型 的DS，以解决这一知识的差距，并探讨直接心脏重塑在SCD中的作用。使用这些 模型，我们将测试的假设，在NaV缺陷的基础遗传性癫痫疾病，如Dravet 综合征，心脏Na+/Ca 2+循环失调，从而促进危及生命的心律失常， 到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Na+/Ca 2+信号传导纳米结构域的功能影响 心脏Ca 2+处理的重塑。3)评估靶向Na+/Ca 2+信号传导纳米结构域对SCD的功效 预防从这些研究中收集的信息将用于开发新的治疗方法， 在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.