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， 发达国家的死亡原因。不幸的是，可以说是最后一个重大的“改变游戏规则”， 心肌细胞电生物学和心脏信号传导对人类健康的突破是β- 阻断剂（在20世纪50年代发现）和“ACE”抑制剂（在20世纪70年代）。另一方面，治疗剂， 治疗心脏兴奋障碍（心律失常）的方法受到疗效有限甚至脱靶的困扰， 心律不齐尽管有大量的负面临床数据，兴奋细胞研究人员在很大程度上仍然 集中在相同的范例-针对心脏离子通道的药理学疗法。我们坚持认为 只有通过更复杂、有效地理解 结构蛋白（如锚蛋白），电蛋白（离子通道，泵和交换器）和信号传导 系统（激酶、磷酸酶、氧化酶）。 我们的研究发现，锚蛋白和血影蛋白，以前认为静态膜 衔接子，在心室肌细胞的离子通道、转运蛋白和信号蛋白靶向中发挥动态作用。 心肌细胞此外，我们已经了解到，这些蛋白质作为关键的中央膜节点， 调节心脏的正常信号传导。最后，也是最重要的，我们已经了解到， 这些传导通路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新的整合机制，调节心血管细胞， 兴奋性和信号传导。我们已经使用锚蛋白和血影蛋白作为一个易于处理的开始信息的情况下 点，但建议迅速扩展这些研究，以新的系统与不同的相互作用的结构，电， 信号系统。我们的实验室在识别新的细胞通路方面处于积极的领先地位， 基于人类临床、组织和遗传数据的细胞兴奋性调节。另外我们有 通过使用生理学相关的模型系统来研究 在复杂的脊椎动物心肌细胞中的潜在电信号机制。这种方法有 最终不仅能够诊断新形式的潜在致命性心律失常， 针对这些疾病的有效患者选择性疗法。如果成功从NHLBI获得资金， 杰出研究者奖，我们将继续追求科学研究，创造新的， 细胞特异性的见解，以提高对心脏兴奋性的理解，与先天性和 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.