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

• 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
• 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

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.

心动过速或心率异常快是心血管疾病发病率和死亡率的重要危险因素。 对于既往无结构性心脏病的患者，长时间心动过速可诱发心肌病。 此外，在心力衰竭患者中经常观察到的短暂性心动过速可加重心血管疾病。 结果。然而，关于心动过速诱导的心脏病的分子驱动因素知之甚少， 功能障碍我们知识上的这一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。K99/R 00提案将利用以下方面的最新进展： 诱导多能干细胞（iPSC）、组织工程和多组学技术来揭示分子 信号传导通路在心动过速相关心脏病的病理学中起关键作用。申请人博士 Chengyi Tu建立并验证了使用工程化心脏组织（EHT）的体外心动过速平台。 在目标1中，Tu博士将在有或没有快速起搏的情况下对EHT进行代谢组学和转录组学分析。到 验证EHT模型的生理相关性，来自快速起搏诱导的心力衰竭的犬样本 也会被分析。来自EHT和犬样本的初步数据一致地表明， 糖酵解稳态的破坏可能是心动过速损害心脏功能的基础。 代谢组学分析表明，EHT中的快速起搏导致糖酵解的选择性积累 中间体如甘油醛3-磷酸（GA 3 P）和3-磷酸甘油酸（3 PG）。有趣的是， 促进脂肪酸代谢可加速心动过速EHT患者心肌收缩力的恢复。基于 在这些新的结果上，目标2将集中于阐明不同的糖酵解中间代谢物如何影响 心肌细胞的功能，这还有待系统地研究。最后，目标3（R 00阶段）将 采用最先进的质谱工作流程来筛选糖酵解的新结合靶点 中间体的心脏细胞，并检查操纵这些目标的潜在治疗效益。这 K99/R 00建议书将由一个具有不同专业知识的优秀指导团队指导，包括导师Dr. Joseph Wu（iPSCs和心脏生物学），共同导师Sanjiv Narayan博士（心律失常），顾问Michael博士 Snyder（遗传学和多组学），Yuqin Dai博士（代谢组学），Stanley Qi博士（CRISPR干扰）和Dr. Beth Pruitt（生物工程），以及合作者Fabio Recchia博士（犬模型）和Donald Bers博士 （心脏生理学）。总括而言，完成建议的研究，将大大促进我们的机制， 了解心动过速如何对心脏产生不利影响，从而为治疗创造新的机会。 干预措施。拟议的培训将大大加强和扩大屠博士的研究专长， 为他向独立心血管研究者的转变提供了巨大的动力。