Tachycardia-induced Metabolic Remodeling Drives Cardiac Dysfunction

心动过速引起的代谢重塑导致心脏功能障碍

基本信息

批准号：
10738875
负责人：
Chengyi Tu
金额：
$ 15.16万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10738875
关键词：
3-Dimensional 3-phosphoglycerate Acceleration Address Adrenergic beta-Antagonists Advisory Committees Affect Animals Arrhythmia Binding Biology Biomedical Engineering Biopsy CRISPR interference Calcium Canis familiaris Cardiac Cardiac Electrophysiologic Techniques Cardiac Myocytes Cardiomyopathies Cardiovascular system Cells Chemicals Coupled Critical Pathways Custom Data Data Engineering Development Enzymes Event Functional disorder Future GTP-Binding Proteins Gene Silencing Genes Genetic Glucose Glyceraldehyde 3-Phosphate Glyceraldehyde-3-Phosphate Dehydrogenases Glycolysis Goals Heart Heart Diseases Heart Rate Heart failure Homeostasis Human Engineering Impairment In Vitro Knowledge Mass Spectrum Analysis Mentors Metabolic Metabolic Diseases Modeling Molecular Morbidity - disease rate Myocardial dysfunction Myoglobin Outcome Oxidative Stress Pathology Pathway interactions Patients Phase Phenotype Phosphoglycerate Kinase Physiological Physiology Play Prognosis Protein Subunits Proteins Proteolysis Qi Recording of previous events Recovery Regulation Research Research Personnel Risk Factors Role Sampling Signal Pathway Sum System Tachyarrhythmias Tachycardia Technology Therapeutic Therapeutic Intervention Tissue Engineering Tissue Model Training Treatment Failure Validation Ventricular Dysfunction analysis pipeline canine model cardiac tissue engineering cardiovascular risk factor design experience fatty acid metabolism feasibility testing heart function human data induced pluripotent stem cell metabolic profile metabolomics mortality multiple omics novel skills small molecule inhibitor stem cell biology structural heart disease transcriptome transcriptome sequencing transcriptomic profiling transcriptomics

项目摘要

Tachycardia, or abnormally fast heart rate, is an important risk factor for cardiovascular morbidity and mortality. Prolonged tachycardia is known to induce cardiomyopathy in patients who have no prior structural heart diseases. Moreover, transient tachycardia, frequently observed in heart failure patients, can exacerbate the cardiovascular outcome. However, very little is known about the molecular drivers underlying tachycardia-induced cardiac dysfunction. This gap in our knowledge hinders the development of more effective heart failure treatment, especially for patients with hard-to-control tachycardia. This K99/R00 proposal will leverage recent advances in induced pluripotent stem cell (iPSC), tissue engineering, and multiomics technologies to uncover the molecular signaling pathways critically involved in the pathology of tachycardia-related heart disease. The applicant, Dr. Chengyi Tu, has established and validated an in vitro tachycardia platform using engineered heart tissue (EHT). In Aim 1, Dr. Tu will perform metabolomic and transcriptomic profiling of EHTs with or without tachypacing. To validate the physiological relevance of the EHT model, canine samples from tachypacing-induced heart failure will also be profiled. Preliminary data from the EHTs and the canine samples coherently indicate that the disruption of glycolysis homeostasis may underly the impairment of cardiac function by tachycardia. Metabolomics analysis shows that tachypacing in EHTs resulted in a selective accumulation of glycolysis intermediates such as glyceraldehyde 3-phosphate (GA3P) and 3-phosphoglycerate (3PG). Interestingly, promotion of fatty acid metabolism accelerated the recovery of cardiac contractility in tachypaced EHTs. Based on these novel results, Aim 2 will focus on elucidating how different glycolysis intermediate metabolites affect the function of cardiomyocytes, which has yet to be systematically examined. Lastly, Aim 3 (R00 phase) will employ state-of-the-art mass spectrometry workflow to screen for novel binding targets of glycolysis intermediates in cardiac cells, and examine the potential therapeutic benefits of manipulating these targets. This K99/R00 proposal will be guided by an excellent mentoring team with diverse expertise, including mentor Dr. Joseph Wu (iPSCs and cardiac biology), co-mentor Dr. Sanjiv Narayan (arrhythmia), advisors Dr. Michael Snyder (genetics and multi-omics), Dr. Yuqin Dai (metabolomics), Dr. Stanley Qi (CRISPR interference) and Dr. Beth Pruitt (bioengineering), as well as collaborators Dr. Fabio Recchia (canine model) and Dr. Donald Bers (cardiac physiology). To sum up, the completion of the proposed study will significantly advance our mechanistic understanding of how tachycardia adversely affects the heart, thereby creating new opportunities for therapeutic interventions. The proposed training will significantly strengthen and expand Dr. Tu’s research expertise, providing substantial momentum to his transition toward an independent cardiovascular researcher.

心动过速或绝对快速心率是心血管发病率和死亡率的重要危险因素。众所周知，长时间的心动过速会诱导没有先前结构性心脏病的患者的心肌病。此外，在心力衰竭患者中经常观察到的短暂性心动过速会加剧心血管结果。但是，关于心动过速诱导的心脏的分子驱动因素知之甚少功能障碍。我们知识的差距阻碍了更有效的心力衰竭治疗的发展特别是对于难以控制的心动过速患者。该K99/R00建议将利用最新进展诱导多能干细胞（IPSC），组织工程和多组学技术，以发现分子信号通路与心动过速相关心脏病的病理非常重要。申请人，博士 Chengyi Tu使用工程心组织（EHT）建立并验证了体外心动过速平台。在AIM 1中，TU博士将进行EHT的代谢组和转录组学分析，无论有或不带有速度。到验证EHT模型的物理相关性，来自tachypacing引起的心力衰竭的犬样品也将被介绍。来自EHT和犬类样本的初步数据一致地表明糖酵解稳态的破坏可能在心动过速受到心脏功能受损下。代谢组学分析表明，EHT中的速度为糖酵解的选择性积累中间体，例如3-磷酸甘油醛（GA3P）和3-磷酸甘油（3pg）。促进脂肪酸代谢加速了速度性EHT中心脏收缩性的恢复。基于在这些新的结果中，AIM 2将重点阐明不同的糖酵解中间代谢产物如何影响心肌细胞的功能尚未系统地检查。最后，AIM 3（R00阶段）将员工最先进的质谱工作流程，以筛选糖酵解的新型结合靶标心脏细胞中的中间体，并检查操纵这些靶标的潜在治疗益处。这 K99/R00提案将由一支出色的心理团队与潜水员专家一起指导，包括心理Dr. Joseph Wu（IPSCS和心脏生物学），同事Sanjiv Narayan博士（心律失常），顾问Michael博士 Snyder（遗传学和多媒体），Yuqin Dai博士（代谢组学），Stanley Qi博士（CRISPR干扰）和博士贝丝·普鲁伊特（Beth Pruitt）（生物工程）以及合作者法比奥·雷奇亚（Fabio Recchia）（犬型）和唐纳德·贝尔斯（Donald Bers）（心脏生理）。总而言之，拟议的研究的完成将大大提高我们的机制了解心动过速如何不利地影响心脏，从而创造新的治疗机会干预措施。拟议的培训将大大加强和扩大Tu博士的研究专业知识，为他向独立心血管研究人员的过渡提供了巨大的动力。