A novel regulator of Ca2+ homeostasis and arrhythmia susceptibility

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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.