A Tbx5-Atp2a2 gene regulatory network for cardiac rhythm - Resubmission 01

心律的 Tbx5-Atp2a2 基因调控网络 - 重新提交 01

• 批准号: 9761177
• 负责人: Sonja Lazarevic
• 金额: $ 4.5万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9761177
• 关键词: ATP2A2; Adult; Affect; Architecture; Arrhythmia; Atrial Fibrillation; Binding; Biological Assay; Biology; CRISPR/Cas technology; Ca(2+)-Transporting ATPase; Calcium; Calcium Signaling; Cardiac Myocytes; Cell physiology; Chromatin; Clinical; Cytosol; Defect; Electrophysiology (science); Endoplasmic Reticulum; Enhancers; Epigenetic Process; Excision; Gap Junctions; Gene Expression; Genes; Genetic; Genetic Transcription; Genome; Heart; Heart Abnormalities; Heart Atrium; Heart failure; Homeostasis; In Vitro; Individual; Laboratories; Lead; Left atrial structure; Luciferases; Maintenance; Mentors; Molecular; Morbidity - disease rate; Mus; Nucleoplasm; Predisposition; Pump; Quantitative Reverse Transcriptase PCR; RNA; RNA Polymerase II; Regulator Genes; Regulatory Element; Risk; RyR2; Sarcoplasmic Reticulum; Stroke; Therapeutic Intervention; United States; Untranslated RNA; Work; deep sequencing; experimental study; genome wide association study; genomic RNA; heart rhythm; insight; interest; knock-down; mortality; mouse model; mutant mouse model; novel; novel strategies; novel therapeutics; promoter; response; side effect; training opportunity; transcription factor

Abstract Atrial Fibrillation (AF) is the most common cardiac arrhythmia and is associated with significant mortality and morbidity. AF is characterized by irregular heartbeats due to random electrical activity in the heart, and affects between 3-5 million individuals in the United States. The clinical and interventional therapies have moderate efficacy and are associated with serious side effects. There is a genetic component to an individual's predisposition for AF that is not fully understood. Therefore, our laboratory is particularly interested in understanding the genetic basis for cardiac arrhythmias, particularly through the identification of relevant gene regulatory networks involved in adult cardiac rhythm. Our lab has found that the deletion of Tbx5 from the adult mouse heart leads to spontaneous AF, therefore establishing the importance of the T-box transcription factor in maintaining atrial rhythm. The deep sequencing of polyA-depleted RNA from wild-type and TBX5-KO left atria identified candidate transcription factor dependent cis-regulatory elements (CREs) for calcium handling genes, including Atp2a2, which were validated in an in vitro luciferase response assay. We are also interested in elucidating the requirement of the ncRNA associated with this CRE. We hypothesize that the Tbx5-dependent ncRNA-defined CRE at Atp2a2, and the ncRNA itself, are required for Atp2a2 expression and cellular calcium homeostasis. Defining these cardiac rhythm regulatory networks may aid in the identification of individuals at risk for arrhythmia, and provide insight into new therapeutic discovery.

摘要 心房颤动（AF）是最常见的心律失常，与显著的死亡率和 发病率AF的特征在于由于心脏中的随机电活动而导致的不规则心跳，并且影响 在美国有300万到500万人临床和介入治疗具有中度 有效性和严重的副作用。一个人的遗传因素 AF的易感性尚未完全了解。因此，我们的实验室特别感兴趣， 了解心律失常的遗传基础，特别是通过识别相关基因 参与成人心律的调节网络。我们的实验室已经发现，Tbx 5从成人中的缺失， 小鼠心脏导致自发性房颤，因此确定了T-box转录因子在 维持心房节律。来自野生型和TBX 5-KO左心房的polyA缺失RNA的深度测序 鉴定了钙处理基因的候选转录因子依赖性顺式调节元件（克雷斯）， 包括Atp 2a 2，其在体外荧光素酶应答测定中得到验证。我们也有兴趣 阐明了与该CRE相关的ncRNA的需求。我们假设Tbx 5依赖性 Atp 2a 2处的ncRNA定义的CRE和ncRNA本身是Atp 2a 2表达和细胞钙离子通道所必需的。 体内平衡定义这些心律调节网络可能有助于识别个体， 心律失常的风险，并提供新的治疗发现的见解。