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.

抽象的 心房颤动（AF）是最常见的心律不齐，与死亡率显着有关 发病率。 AF的特征是由于心脏中随机电活动而导致心跳不规则，并影响 在美国，有3-5万个人。临床和介入疗法中等 功效，与严重的副作用有关。一个人的遗传成分 尚未完全理解的AF的易感性。因此，我们的实验室对 了解心律不齐的遗传基础，特别是通过鉴定相关基因 与成人心律有关的监管网络。我们的实验室发现，从成年人删除TBX5 小鼠心脏会导致自发的AF，因此确定了T-box转录因子的重要性 保持心律。从野生型和TBX5-KO的polya耗尽的RNA的深度测序使心房 钙处理基因的鉴定候选转录因子依赖于顺式调节元件（CRE）， 包括在体外荧光素酶反应测定中验证的ATP2A2。我们也对 阐明与此Cre相关的NCRNA的要求。我们假设TBX5依赖性 ATP2A2处的NCRNA定义的CRE和NCRNA本身是ATP2A2表达和细胞钙所必需的 稳态。定义这些心律调节网络可能有助于确定个人 心律不齐的风险，并深入了解新的治疗发现。