Metabolic regulation of heart formation

项目总结/摘要 体外培养的干细胞的不成熟是阻碍人类心脏干细胞生物学成功应用的主要障碍 细胞衍生的心肌细胞。干细胞衍生的心肌细胞的遗传操作在心肌细胞中尚未成功。 达到足够成熟的再生医学，药物筛选，疾病建模和发展 生物学最近的多中心研究揭示了非遗传因素对发展的重要性， 先天性心脏病因此，在体外和体内环境中，非遗传因素是研究不足的领域。 研究可以，结合丰富的知识，在遗传贡献心脏发生， 解决干细胞衍生的心肌细胞的不成熟问题。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，母体高血糖与 先天性心脏病的风险显著增加。然而，关于高血糖是否 直接影响心肌细胞的分化，以及高葡萄糖如何影响下游细胞的流动。 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的调节。 细胞在胎儿心脏中，葡萄糖通过转运蛋白亚型1和4被摄取，并通过多个转运蛋白被加工。 分解代谢和合成代谢途径，包括糖酵解、TCA、戊糖磷酸途径、己糖胺途径等。 我们用人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，在胎儿期调节心脏发生中起主要作用。这些结果导致我们的中央 假设葡萄糖通过核苷酸生物合成抑制胎儿心脏成熟。本提案将通过以下方式对其进行测试： 体内和体外的遗传、代谢和生理分析。预计结果将证明， 胎儿心脏的代谢环境不仅是遗传分化程序的结果， 心脏发育成熟。通过关注心脏发生研究的不足领域，这项研究将增加另一个 我们对心脏发生和先天性心脏病的理解。

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.