Defining novel mechanisms for human arrhythmia

摘要 心脏兴奋性缺陷是人类心律失常和心脏性猝死的基础，而心脏兴奋性缺陷是导致人类心律失常和心脏性猝死的主要原因 发达国家的死亡原因。不幸的是，可以说，这是最后一次改变游戏规则的重大事件 电心肌细胞生物学和心脏信号对人类健康的突破是 阻滞剂(发现于1950年代)和‘ACE’抑制剂(发现于1970年代)。另一方面，治疗剂可以 治疗心脏兴奋障碍(心律失常)的疗效有限，甚至偏离靶点。 心律不齐。尽管有大量的负面临床数据，但兴奋的细胞研究人员基本上仍然 专注于相同的范式--针对心脏离子通道的药物治疗。我们认为 改进的疗法只有通过更复杂、更有效地理解 结构蛋白(如粘蛋白)、电蛋白(离子通道、泵和交换器)和信号传递 系统(激酶、磷酸酶、氧化物酶)。 我们的研究发现，锚蛋白和幽灵蛋白，以前被认为是静态膜 适配器在心室离子通道、转运体和信号蛋白靶向中扮演动态角色 心肌细胞。此外，我们了解到，这些蛋白质作为关键的中央膜节点作用于 调节心脏内的正常信号。最后，也是最重要的是，我们已经了解到这些细胞的功能障碍 这些途径导致先天性和获得性室性心律失常的潜在致命形式。 我们的长期目标是发现调节心血管细胞的新的综合机制 兴奋性和信号。我们已经使用了Anyrins和Spectrin的信息性案例作为一个容易处理的开始 点，但建议迅速将这些研究扩展到具有不同相互作用结构的新系统-电子- 信号系统。我们的实验室在鉴定新的细胞通路方面发挥了积极的作用 基于人类临床、组织和遗传数据的细胞兴奋性调节。此外，我们还有 通过使用与生理相关的模型系统来研究 复杂脊椎动物心肌细胞中潜在的电信号机制。这种方法具有 最终达到顶峰的不仅是诊断新的潜在致命心律失常的能力，而且是设计 针对这些疾病的有效的患者选择疗法。如果成功从NHLBI获得资金 杰出研究员奖，我们将继续从事科学研究，有潜力创造新的， 改善对心脏兴奋性的理解与先天性和先天性心脏病的直接相关性的细胞特异性见解 获得性人类疾病。

Abstract Defects in cardiac excitability are the basis for human arrhythmia and sudden cardiac death, a leading cause of mortality in developed countries. Unfortunately, arguably the last major “game-changing” breakthroughs in electrical cardiomyocyte biology and cardiac signaling for human health were the beta- blocker (discovered in the 1950s) and `ACE' inhibitor (in the 1970s). On the other hand, therapeutic agents to treat disorders of cardiac excitation (arrhythmias) are plagued by limited efficacy and even off-target pro- arrhythmia. Despite a wealth of negative clinical data, excitable cell researchers have largely remained focused on the same paradigm - pharmacological therapies targeting cardiac ion channels. We contend that improved therapies will only arise through a more sophisticated, working understanding of interactions between structural proteins (such as ankyrins), electrical proteins (ion channels, pumps & exchangers) and signaling systems (kinases, phosphatases, oxidases). Our studies discovered that ankyrin and spectrin proteins, previously considered static membrane adapters, play dynamic roles in ion channel, transporter, and signaling protein targeting in ventricular cardiomyocytes. Further, we have learned that these proteins serve as critical central membrane nodes to regulate normal signaling in heart. Finally, and most importantly, we have learned that dysfunction in these pathways results in potentially fatal forms of both congenital and acquired ventricular arrhythmia. Our long-term goal is to discover novel integrated mechanisms for regulating cardiovascular cell excitability and signaling. We have used the informative case of ankyrins and spectrins as a tractable starting point, but propose to rapidly extend these studies to new systems with diverse interacting structure-electrical- signaling systems. Our laboratory has taken an active lead in the identification of new cellular pathways for regulation of cellular excitability based on human clinical, tissue, and genetic data. In addition, we have pushed innovation in the field through the use of physiologically-relevant model systems to study the mechanisms underlying electrical signaling in the complex vertebrate cardiomyocyte. This approach has ultimately culminated in an ability to not only diagnose new forms of potentially fatal arrhythmia, but to design effective patient-selective therapies for these diseases. If successful in obtaining funding from the NHLBI Outstanding Investigator Award, we will continue to pursue scientific studies with the potential to create new, cell-specific insights for improved understanding of cardiac excitability with direct relevance for congenital and acquired human disease.