Mapping metabolic activities in stem cell-derived models of human cardiomyopathy

绘制人类心肌病干细胞衍生模型的代谢活动图谱

基本信息

批准号：
9170227
负责人：
Mohit Jain
金额：
$ 7.75万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-15 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9170227
关键词：
Advanced Development American Automobile Driving Award Big Data Bioenergetics Biological Markers Biological Models Calcium Cardiac Cardiac Myocytes Cardiomyopathies Cardiovascular Diseases Cell model Cells Complex Computational Science Congenital cardiomyopathy Coupled Development Diagnosis Dietary Intervention Dilated Cardiomyopathy Enzymes Epidemic Foundations Frequencies Funding Future Generations Genes Genetic Global Change Heart Heart Injuries Heart failure Human Hypertrophic Cardiomyopathy In Vitro Individual Injury Institutes Journals Laboratories Maps Mass Spectrum Analysis Measures Metabolic Metabolic Pathway Metabolism Modeling Myocardial Myocardial dysfunction Nature Organ Pathogenesis Pathology Patients Performance Phenotype Physiological Physiology Prevalence Process Publications Research Personnel Rodent Rodent Model Role Sampling Stem cells Stress Systems Biology Toxicology Training Up-Regulation Ventricular Work base cell type drug development fatty acid oxidation fetal glucose metabolism heart dimension/size human disease in vivo induced pluripotent stem cell insight interest liquid chromatography mass spectrometry metabolic abnormality assessment metabolomics novel strategies personalized therapeutic programs research study response stem cell technology

项目摘要

PROJECT SUMMARY Despite advances in the diagnosis and treatment of cardiovascular disease, the prevalence of heart failure continues to rise at epidemic rates. In response to varied injuries, the heart undergoes a complex process of remodeling, marked by upregulation of a fetal expression program and corresponding switching of metabolic activity to a fetal-like state, in close association with the development of cardiomyopathy. Over the course of the initial K08 funding period the Applicant trained in technical mass spectrometry based metabolomics and computational sciences, and their collective application to interrogate substrate utilization in cells in culture, metabolic measures of organ level physiology, and shifts in metabolic enzyme expression. Moreover, Applicant has applied these approaches to characterize the metabolic remodeling that occurs during the pathogenesis of heart failure, identifying previously unrecognized metabolic activities in the heart. These metabolic studies, however, have been limited to rodent models of myocardial injury, and it remains unclear to what extend these models recapitulate the development of human heart failure, particularly given critical differences in cardiac size, physiology, and bioenergetics between human and rodent cardiomyocytes. The development and advance of human induced pluripotent stem cells (iPSC) technologies has transformed the study of human disease. Human iPSCs may be readily differentiated into ventricular cardiomyocytes (iPSC-CMs) in vitro at high efficiencies and have been found to recapitulate in vivo human phenotypes across a number of genetic cardiomyopathies, with impaired calcium handling, decreased force generation, and re-expression of the metabolic fetal gene program. In this R03 proposal, the Applicant now aims to extend upon the initial K08 award, and apply comprehensive metabolomics to the study of human cardiomyopathy, in an effort to decipher the metabolic underpinnings of human heart failure. Using iPSC-CMs derived from patients with sequence- verified familial cardiomyopathies (dilated and hypertrophic cardiomyopathy) the Applicant will comprehensively define the metabolic changes that occur with cardiac pathology through state-of-the-art liquid chromatography - mass spectrometry. These proposed studies will shed tremendous insight into the metabolic basis for human cardiomyopathy, distinguish new metabolite biomarkers for impaired contractile activity, and identify metabolic pathways amenable to pharmacologic and dietary intervention, as well as will form the foundation for the Applicant's transition to an independent, R01 funded investigator.

项目概要尽管心血管疾病的诊断和治疗取得了进步，但心力衰竭的患病率仍然很高流行率继续上升。为了应对各种损伤，心脏会经历一个复杂的过程：重塑，以胎儿表达程序的上调和相应的代谢转换为标志活动达到胎儿样状态，与心肌病的发展密切相关。整个过程中在最初的 K08 资助期间，申请人接受了基于代谢组学技术质谱分析的培训，并且计算科学及其在培养细胞中探究底物利用率的集体应用，器官水平生理学的代谢测量，以及代谢酶表达的变化。此外，申请人应用这些方法来表征发病过程中发生的代谢重塑心力衰竭，识别心脏中以前未被识别的代谢活动。这些代谢研究，然而，仅限于心肌损伤的啮齿动物模型，目前尚不清楚这些研究的范围模型概括了人类心力衰竭的发展过程，特别是考虑到心脏功能的关键差异人类和啮齿动物心肌细胞的大小、生理学和生物能学。发展与人类诱导多能干细胞（iPSC）技术的进步改变了人类的研究疾病。人类 iPSC 在体外可轻易分化为心室心肌细胞 (iPSC-CM) 高效率，并已被发现可以重现体内多种遗传的人类表型心肌病，钙处理受损，力量产生减少，以及心肌细胞的重新表达代谢胎儿基因程序。在这个 R03 提案中，申请人现在的目标是扩展最初的 K08 奖，并将综合代谢组学应用于人类心肌病的研究，以期破译人类心力衰竭的代谢基础。使用来自具有序列的患者的 iPSC-CM 经证实的家族性心肌病（扩张型和肥厚型心肌病），申请人将通过最先进的液体全面定义心脏病理学中发生的代谢变化色谱-质谱法。这些拟议的研究将深入了解代谢人类心肌病的基础，区分收缩活动受损的新代谢生物标志物，以及确定适合药物和饮食干预的代谢途径，并将形成申请人转变为独立的、R01 资助的研究者的基础。