A novel regulator of Ca2+ homeostasis and arrhythmia susceptibility

项目摘要 心房颤动（AF）是临床上最常见的心律失常，具有很强的遗传性。 AF患者存在发生使人衰弱的并发症的显著风险，如中风、心力衰竭和突发性心脏病。 死亡新出现的证据表明，心脏转录因子中常见和罕见的遗传变异 有助于房颤易感性。转录因子和AF之间的这种联系提供了令人兴奋的机会， 研究以前未被认识的途径，以确定新的“上游”治疗靶点。我们最近 在一个常染色体遗传性房颤家族中，发现心脏转录因子NFATC 1是一个新的房颤易感基因。 该提案的总体目标是探索分子和电生理 NFATC 1在心脏兴奋性中的作用。我们的中心假设是NFATC 1直接调节相关基因， 维持心房内钙的稳态。我们提出了三个具体目标来检验这一假设：（1） 鉴定与心房钙稳态相关的NFATC 1转录效应子;（2）建立 心房细胞中NFATC 1破坏的电生理学后果;以及（3）定义心房细胞中NFATC 1的调节。 心脏中的肾上腺素信号。该项目的产出将是对 由NFATC 1介导的影响钙稳态和促进肿瘤发生的转录网络， 为未来的潜在疗法奠定基础。 在这个职业指导奖提出的研究活动将提供经验学习，以支持 我的职业发展目标这些包括（1）将我的技能扩展到基因组学研究，光学 绘制更适合研究心律失常的动物模型;（2）加强研究 领导和管理技能，以及（3）提高我的能力，以确保独立的资金。 实现这些目标将使我能够发展作为一个独立的首席研究员的研究生涯， 多学科心血管研究实验室，为了解 心脏病的发展。

PROJECT ABSTRACT Atrial fibrillation (AF) is the most common clinical cardiac arrhythmia, with a strong component of heritability. Patients with AF are at significant risk for debilitating complications, such as stroke, heart failure and sudden death. Emerging evidence suggests that both common and rare genetic variants in cardiac transcription factors contribute to AF susceptibility. This link between transcription factors and AF offers exciting opportunities to investigate previously unrecognized pathways to identify novel “upstream” therapeutic targets. We recently identified the cardiac transcription factor NFATC1 as a novel AF susceptibility gene in a family with autosomal dominant young-onset AF. The overall goal of this proposal is to explore the molecular and electrophysiological role of NFATC1 in cardiac excitability. Our central hypothesis is that NFATC1 directly regulates genes involved in maintaining calcium homeostasis in the atrium. We proposed three specific aims to test this hypothesis: (1) identify NFATC1 transcriptional effectors linked to calcium homeostasis in atria; (2) establish the electrophysiological consequences of NFATC1 disruption in atrial cells; and (3) define NFATC1 modulation of adrenergic signaling in the heart. The output of this project will be a comprehensive understanding of the transcriptional networks mediated by NFATC1 that impact calcium homeostasis and promote arrhythmogenesis, laying the foundation for potential future therapies. The research activities proposed in this career mentored award will provide experiential learning in support of my career development objectives. These include (1) expanding my skills into genomics research, optical mapping and new animal models that are more suitable for the study of arrhythmias, (2) strengthen my research leadership and management skills, and (3) enhance my grantsmanship to secure independent funding. Achieving these goals will allow me to develop a research career as an independent principal investigator of a multidisciplinary cardiovascular research lab that makes substantial contributions to understanding the development of heart disease.