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.

项目概要/摘要 人类心脏干细胞生物学成功应用的主要障碍是体外干细胞的不成熟 细胞来源的心肌细胞。干细胞衍生的心肌细胞的基因操作尚未成功 达到再生医学、药物筛选、疾病建模和发育的足够成熟度 生物学。最近的多中心研究揭示了非遗传因素对发育的重要性 先天性心脏病。因此，在体外和体内环境中，非遗传因素都是未充分研究的领域。 研究与心脏发生的遗传贡献者的丰富知识相结合，有可能 解决干细胞来源的心肌细胞不成熟的问题。事实上，代谢/营养环境是一个 影响心脏形成的主要非遗传因素。众所周知，母亲高血糖与 先天性心脏病的风险显着增加。然而，对于高血糖是否 直接影响心肌细胞的分化以及高血糖对下游细胞流动的影响 代谢途径。葡萄糖是细胞最重要的营养物质，其代谢在任何细胞中都受到严格调节。 细胞。在胎儿心脏中，葡萄糖通过转运蛋白同种型 1 和 4 吸收，并通过多种途径进行处理。 分解代谢和合成代谢途径包括糖酵解、TCA、磷酸戊糖途径、己糖胺途径等。 我们对人类胚胎干细胞衍生的心肌细胞和糖尿病小鼠模型的初步数据 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 葡萄糖在胎儿阶段的心脏发生调节中起主要作用。这些结果促使我们中央 葡萄糖通过核苷酸生物合成抑制胎儿心脏成熟的假设。该提案将通过以下方式进行测试： 体内和体外遗传、代谢和生理分析。预计结果将证明独特的 胎儿心脏的代谢环境不仅是遗传分化程序的结果，也是驱动因素 心脏的成熟。通过关注心脏发生研究的未充分研究领域，本研究将增加另一个 我们对心脏发生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