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