Genes and Metabolism: Targeting Mitochondrial Dysfunction in Atrial Fibrillation

项目2概要 心房颤动（AF）风险会因各种心血管应激因素而增加，包括肥胖、高血压、 冠状动脉或瓣膜疾病，心力衰竭，代谢综合征，睡眠呼吸暂停，过度饮酒， 用力。AF是一种进行性疾病，随着AF的增加，中风和其他并发症的风险也会增加 负担识别可以减缓或逆转AF进展的药物或干预措施将具有 重大临床影响。在RNA测序研究中，我们已经确定了线粒体功能障碍， 氧化磷酸化途径中最突出的途径与发展的 持续性房颤。在项目2，基因和代谢：靶向心房颤动中的线粒体功能障碍 (P2)，我们的中心假设是代谢应激源和衰老增加了线粒体氧化剂的产生， 促进心房线粒体DNA损伤、功能障碍和代谢异质性。我们假设 代谢异质性是电不稳定性的基础，促进线粒体 弹性和有限代谢异质性将减少心房异位和减缓AF进展。我们提出了两 具体目标。目的1旨在评估代谢应激源在体外工程心脏模型中的作用 组织（EHT），来源于人诱导多能干细胞分化的心房样心肌细胞 细胞我们将研究4种不同的代谢应激因子对转录和功能的影响， 房颤病因对人心房肌EHT细胞组成及线粒体、收缩和电功能的影响 八应激源包括：长期暴露于异丙肾上腺素、棕榈酸酯、乙醇和内皮素-1; 应激源将用于测试代谢/线粒体靶向药物在EHT中的保护作用。在目标2中， 我们将评估杂合子CREM-Ib型房颤患者房颤进展的代谢机制。 自发性AF和AF进展的转基因小鼠模型，采用高脂肪饮食作为代谢调节剂。 我们可以研究肥胖对发育和发育的功能和转录组影响的压力 我们假设在该模型中AF的进展也是由线粒体介导的。 功能障碍，导致代谢、转录和电生理功能障碍。因此，我们建议， 肥胖小鼠将比瘦的转基因小鼠更快、更早地发展AF，并且负担更大。 最后，使用肥胖转基因小鼠，我们将评估保护EHT的药物的影响， 线粒体功能障碍和下游效应，以确定这些药物是否可以减缓发展， 我们期望心房EHT和肥胖CREM-Ib/CX小鼠模型都将用于 临床前测试新的和现有的代谢药物，可以改善AF治疗和减缓其进展。 该项目与PPG的其他项目高度合作，并将有助于实现这一总体目标。 PPG推进治疗，可以减缓进展并减轻房颤的负担。

PROJECT 2 SUMMARY Atrial fibrillation (AF) risk is increased by a variety of cardiovascular stressors, including obesity, hypertension, coronary or valve disease, heart failure, metabolic syndrome, sleep apnea, excessive alcohol, and extreme exertion. AF is a progressive condition, and risk of stroke and other complications increases with increasing AF burden. Identification of drugs or interventions that can slow or reverse the progression of AF would have a significant clinical impact. In RNA sequencing studies, we have identified mitochondrial dysfunction and oxidative phosphorylation pathways among the most prominent pathways associated with development of persistent AF. In Project 2, Genes and Metabolism: Targeting Mitochondrial Dysfunction in Atrial Fibrillation (P2), our central hypothesis is that metabolic stressors and aging increase mitochondrial oxidant production, promoting atrial mitochondrial DNA damage, dysfunction and metabolic heterogeneity. We hypothesize that metabolic heterogeneity underlies electrical instability, and that interventions that promote mitochondrial resilience and limit metabolic heterogeneity will reduce atrial ectopy and slow AF progression. We propose two specific aims. Aim 1 seeks to evaluate the role of metabolic stressors on an in vitro model of engineered heart tissues (EHTs), derived from atrial-like cardiac myocytes differentiated from human induced pluripotent stem cells. We will study the transcriptional and functional impact of 4 distinct metabolic stressors relevant to the etiology of AF on EHT cellular composition and mitochondrial, contractile and electrical function of human atrial EHTs. Stressors include: chronic exposure to isoproterenol, palmitate, ethanol and endothelin-1; the same stressors will be used to test the protective effect of metabolic/mitochondrial targeted drugs in EHTs. In Aim 2, we will evaluate the metabolic mechanisms that underlie progression of AF in the heterozygous CREM-IbCX transgenic mouse model of spontaneous AF and AF progression, employing a high fat diet as a metabolic stress with which we can study the functional and transcriptomic impact of obesity on the development and rate of progression of AF. We hypothesize that progression of AF in this model is also caused by mitochondrial dysfunction, resulting in metabolic, transcriptional and electrophysiologic dysfunction. We thus propose that obese mice will develop AF more quickly, earlier, and with a greater burden than in lean transgenic mice. Finally, using obese transgenic mice, we will evaluate the impact of drugs that protected EHTs from mitochondrial dysfunction and downstream effects, to determine if these drugs can slow the development and progression of AF. We expect both the atrial EHT and obese CREM-IbCX mouse models will be useful for preclinical testing of new and existing metabolic drugs that can improve AF treatment and slow its progression. This project is highly collaborative with the other PPG projects, and will contribute to the overall goal of this PPG to advance therapies that can slow the progression and reduce the burden of atrial fibrillation.