Effects of the atrial fibrillation risk region on chromosome 4q25 and PITX2 on atrial metabolic and mitochondrial function

染色体4q25和PITX2上房颤危险区对心房代谢和线粒体功能的影响

• 批准号: 509167694
• 负责人: Professorin Dr. Friederike Cuello
• 金额: --
• 依托单位: Institut für Experimentelle Pharmakologie und Toxikologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/509167694?language=en
• 关键词: Effects; atrial; fibrillation; risk; region

Atrial fibrillation (AF) affects at least 2% of the population in Germany. It is a highly prevalent risk factor for cardiovascular deaths, stroke, heart failure, and acute coronary syndromes in patients. Common gene variants on chromosome 4q25 show by far the strongest genomic association with AF risk in the population. These risk variants reside in an enhancer region controlling transcription of the Paired like Homeodomain 2 (PITX2) gene via long-range chromatin interactions. PITX2 expression is largely confined to the left atrium in the adult heart. Enhancer deletion including these risk variants leads to reduced atrial PITX2 expression in mice and in patients to recurrent AF after ablation, predisposition to AF by modifying electrical function of the atria and alterations in atrial electrical and contractile function. To understand the molecular mechanisms of this atrial disease phenotype, the present project aims to characterize the electrophysiological and metabolic consequences of enhancer deletion in a knockin-in mouse and in genetically-engineered enhancer deleted human induced pluripotent stem cell-derived atrial cardiomyocyte (atrial hiPSC-EHTs) model cultured in a three-dimensional tissue culture format. Experiments will involve echocardiography and optical pacing in mice as well as contractile analysis during nutrient-restriction in atrial hiPSC-EHTs combined with unbiased transcriptomic and metabolic analysis. The results are anticipated to enhance our understanding of underlying AF disease mechanisms and might inspire novel treatment strategies.

在德国，房颤（AF）影响至少2%的人口。它是患者心血管死亡、中风、心力衰竭和急性冠状动脉综合征的一个非常普遍的风险因素。到目前为止，染色体4 q25上的常见基因变异显示出与人群中AF风险最强的基因组关联。这些风险变体存在于增强子区域，通过长距离染色质相互作用控制配对样同源结构域2（PITX 2）基因的转录。PITX 2的表达主要局限于成人心脏的左心房。包括这些风险变体的增强子缺失导致小鼠和消融后复发性AF的患者中心房PITX 2表达减少，通过改变心房的电功能和心房电和收缩功能的改变而易患AF。为了了解这种心房疾病表型的分子机制，本项目旨在表征在敲入小鼠和在三维组织培养格式中培养的基因工程增强子缺失的人诱导多能干细胞衍生的心房心肌细胞（心房hiPSC-EHTs）模型中增强子缺失的电生理和代谢后果。实验将涉及小鼠中的超声心动图和光学起搏以及心房hiPSC-EHT中营养限制期间的收缩分析，并结合无偏转录组学和代谢分析。这些结果有望增强我们对潜在房颤疾病机制的理解，并可能激发新的治疗策略。