Metabolic regulation of heart formation

心脏形成的代谢调节

• 批准号: 10459280
• 负责人: Atsushi Nakano
• 金额: $ 39万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10459280
• 关键词: Adult; Area; Biological Assay; Birth; Blood Glucose; Cardiac; Cardiac Myocytes; Cell Differentiation process; Cell Proliferation; Cells; Characteristics; Chemicals; Citric Acid Cycle; Critical Pathways; Cues; DNA Sequence Alteration; Data; Development; Developmental Biology; Dimensions; Disease model; Dissection; Dose; Drug Screening; Electrophysiology (science); Embryo; Energy-Generating Resources; Environment; Exposure to; Fatty Acids; Fetal Heart; Genetic; Genetic Drift; Glucose; Glucose Transporter; Glycolysis; Goals; Heart; Hexosamines; Human; Hyperglycemia; In Vitro; Knowledge; Lead; Measurement; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Modeling; Morphology; Multicenter Studies; Mus; Neonatal; Nucleotide Biosynthesis; Nucleotides; Nutrient; Nutritional; Organ; Oxidative Phosphorylation; Pathway interactions; Patients; Pediatric Cardiac Genomics Consortium; Pentosephosphate Pathway; Physiological; Play; Pregnancy; Process; Production; Protein Isoforms; Reaction; Regenerative Medicine; Regulation; Research; Risk; Rodent; Role; Source; Structure; Supplementation; Testing; cardiogenesis; cell type; congenital heart disorder; diabetic; differentiation protocol; drug development; fatty acid oxidation; fetal; fetal blood; fluorodeoxyglucose; genetic approach; genetic manipulation; glucose uptake; human embryonic stem cell; human pluripotent stem cell; in vivo; induced pluripotent stem cell derived cardiomyocytes; insight; maternal hyperglycemia; monolayer; mouse model; mutant; non-genetic; novel; programs; research study; self-renewal; stem; stem cell biology; stem cells; uptake

PROJECT SUMMARY/ABSTRACT The major obstacle to the successful application of human cardiac stem cell biology is the immaturity of in vitro stem cell-derived cardiomyocytes. Genetic manipulations of stem cell-derived cardiomyocytes have not been successful in achieving the maturity sufficient for regenerative medicine, drug screening, disease modeling and developmental biology. Recent multi-center study revealed the importance of non-genetic contributors to the development of congenital heart disease. Thus, in both in vitro and in vivo settings, non-genetic factors are understudied area of research that can, combined together with the wealth of knowledge in genetic contributors to cardiogenesis, potentially solve the immaturity issue of stem cell-derived cardiomyocytes. In fact, the metabolic/nutritional environment is a major non-genetic factor that impact heart formation. It is well-established that maternal hyperglycemia is associated with significant increase in the risk of congenital heart disease. However, little is known about whether high glucose directly impact the differentiation of cardiomyocytes and how high glucose might impact the flow of downstream metabolic pathways. Glucose is the most critical nutrients to the cells and its metabolism is tightly regulated in any cells. In the fetal heart, glucose is taken up through transporter isoforms 1 and 4 and processed through multiple catabolic and anabolic pathways including glycolysis, TCA, pentose phosphate pathway, hexosamine pathway, etc. Our preliminary data with human embryonic stem cell-derived cardiomyocytes and murine model of diabetic pregnancy suggest that it is not the catabolic extraction of energy but the anabolic biosynthesis of nucleotides from glucose that plays a major role in regulating cardiogenesis during fetal stage. These results have led to our central hypothesis that glucose inhibits fetal cardiac maturation via nucleotide biosynthesis. This proposal will test it by genetic, metabolic, and physiological analyses in vivo and in vitro. The results are expected to demonstrate that unique metabolic environment of fetal heart is not merely a consequence of genetic differentiation program but also a driver of cardiac maturation. By focusing on understudied area of cardiogenesis research, this study will add another dimension to our understanding of cardiogenesis and congenital heart disease.

项目摘要/摘要 成功应用人类心脏干细胞生物学的主要障碍是体外茎的不成熟 细胞来源的心肌细胞。干细胞衍生的心肌细胞的遗传操作尚未成功 实现足以用于再生医学，药物筛查，疾病建模和发育的成熟度 生物学。最近的多中心研究揭示了非基因贡献者对发展的重要性 先天性心脏病。因此，在体外和体内环境中，非遗传因素都是研究的 可以将可以与心脏病的遗传贡献者相结合的研究，并有可能 解决了干细胞衍生的心肌细胞的不成熟问题。实际上，代谢/营养环境是 影响心脏形成的主要非遗传因素。良好的表明母体高血糖与之相关 先天性心脏病的风险显着增加。但是，关于高葡萄糖是否了解 直接影响心肌细胞的分化以及葡萄糖可能影响下游流动的高度 代谢途径。葡萄糖是细胞最关键的营养素，其代谢受到任何在任何中的调节 细胞。在胎儿心脏中，葡萄糖通过转运蛋白同工型1和4吸收，并通过多个处理 分解代谢和合成代谢途径在内 我们使用人类胚胎干细胞衍生的心肌细胞和糖尿病的鼠模型的初步数据 怀孕表明，这不是能量的分解代谢提取，而是核苷酸的合成代谢生物合成。 在调节胎儿阶段的心脏发生中起主要作用的葡萄糖。这些结果导致了我们的中心 葡萄糖通过核苷酸生物合成抑制胎儿心脏成熟的假设。该建议将通过 在体内和体外进行遗传，代谢和生理分析。结果预计将证明独特 胎儿心脏的代谢环境不仅是遗传分化计划的结果，而且是驱动因素的结果 心脏成熟。通过专注于心脏病研究研究的研究领域，这项研究将增加另一项 我们对心脏病和先天性心脏病的理解的维度。

项目成果

A novel murine model of atrial fibrillation by diphtheria toxin-induced injury.

• DOI: 10.3389/fphys.2022.977735
• 发表时间: 2022
• 期刊: FRONTIERS IN PHYSIOLOGY
• 影响因子: 4
• 作者: Trieu, Theresa;Mach, Philbert;Bunn, Kaitlyn;Huang, Vincent;Huang, Jamie;Chow, Christine;Nakano, Haruko;Fajardo, Viviana M.;Touma, Marlin;Ren, Shuxun;Wang, Yibin;Nakano, Atsushi
• 通讯作者: Nakano, Atsushi