A novel regulator of Ca2+ homeostasis and arrhythmia susceptibility

Ca2 稳态和心律失常易感性的新型调节剂

• 批准号: 10724935
• 负责人: Natalia Torres
• 金额: $ 13.4万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10724935
• 关键词: ATAC-seq; Action Potentials; Active Learning; Acute; Adolescent; Adrenergic Agents; Adult; Animal Model; Arrhythmia; Atrial Fibrillation; Automobile Driving; Award; CRISPR/Cas technology; Calcium; Cardiac; Cardiac Myocytes; Cardiovascular system; Cell Nucleus; Cells; Chromatin; Chronic; Clinical; Data; Development; Down-Regulation; Economic Burden; Electrophysiology (science); Event; Family; Fishes; Foundations; Functional disorder; Funding; Future; Gene Deletion; Gene Silencing; Genes; Genetic Predisposition to Disease; Genetic Transcription; Genomics; Goals; Healthcare Systems; Heart; Heart Atrium; Heart Diseases; Heart failure; Heritability; Homeostasis; Hospital Costs; Human; Individual; Ion Channel; Knowledge; Leadership; Link; Maintenance; Maps; Measures; Mediating; Mentors; Mission; Modeling; Molecular; Morbidity - disease rate; Optics; Output; Pathogenesis; Pathway interactions; Patients; Predisposition; Prevalence; Principal Investigator; Property; Regulation; Regulator Genes; Regulatory Pathway; Research; Research Activity; Risk; Role; Sarcoplasmic Reticulum; Secure; Signal Transduction; Small Interfering RNA; Stress; Stroke; Sudden Death; Susceptibility Gene; Tachyarrhythmias; Testing; Transcript; Transgenic Organisms; Tretinoin; United States National Institutes of Health; Western Blotting; Zebrafish; autosome; career; career development; clinical practice; genetic variant; induced pluripotent stem cell derived cardiomyocytes; insight; mortality; multidisciplinary; multiple omics; novel; novel therapeutic intervention; pharmacologic; response; single-cell RNA sequencing; skills; stressor; targeted treatment; therapeutic target; therapeutically effective; transcription factor; transcription factor USF; transcriptional reprogramming; transcriptome sequencing

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.

项目摘要 心房颤动（AF）是最常见的临床心律不齐，具有强大的遗传力。 AF患者有严重的衰弱并发症的风险，例如中风，心力衰竭和突然 死亡。新兴证据表明，心脏转录因子中的常见和稀有遗传变异 有助于AF易感性。转录因素和AF之间的这种联系为您提供了令人兴奋的机会 研究先前无法识别的途径，以识别新型的“上游”治疗靶标。我们最近 将心脏转录因子NFATC1识别为常染色体家族中的新型AF敏感性基因 占主导地位的AF。该建议的总体目标是探索分子和电生理 NFATC1在心脏兴奋性中的作用。我们的中心假设是NFATC1直接调节所涉及的基因 在中庭维持钙稳态。我们提出了三个特定的目的来检验这一假设：（1） 确定与心房中钙稳态相关的NFATC1转录效应； （2）建立 心房细胞中NFATC1破坏的电生理后果； （3）定义NFATC1调制 心脏中的肾上腺素信号传导。该项目的输出将是对 由NFATC1介导的转录网络影响钙稳态并促进心律失常发生， 为潜在的未来疗法奠定基础。 本职业事务奖提出的研究活动将提供专家学习，以支持 我的职业发展目标。其中包括（1）将我的技能扩展到基因组学研究，光学 映射和新的动物模型更适合于心律不齐，（2）加强我的研究 领导和管理技能，以及（3）增强我的赠款技巧以获得独立的资金。 实现这些目标将使我能够发展研究职业 多学科心血管研究实验室，为理解 心脏病的发展。