Developmental Control of Metabolism

描述 摘要： 本研究将以小鼠早期胚胎及其衍生的胚胎干细胞为模型，探讨发育过程中代谢途径、线粒体活性和生物发生的调控。这一提议是基于代谢活动对人类健康和疾病的重要性，以及相对缺乏关于在发育阶段控制各种代谢活动模式之间过渡的机制的数据。核和线粒体活动不断相互调节，并在发育，癌症和干细胞维持过程中通常研究的信号转导途径与代谢途径，如氧化磷酸化，糖酵解，线粒体生物合成和营养传感之间的关系将被探索。所涉及的技术将需要在体内标记与代谢相关的基因，然后在小鼠发育的非常早期阶段研究代谢基因活性的进展。随后将从这些胚胎中分离ES细胞，并通过干扰各种信号通路，确定对它们代谢状态的影响。这一奋进的首要目标是了解氧化和糖酵解活性之间的瓦尔堡效应样转变的发育控制的分子机制;并充分了解哺乳动物发育过程中细胞核和神经元之间串扰的性质。该模型与人类干细胞生物学和癌症研究相关。 公共卫生相关性： 这项建议从很多不同的角度来看都与公共卫生有关。代谢紊乱具有重要意义，其研究构成了该建议的核心。然而，正是对代谢途径与癌症和发育缺陷相关的代谢途径相互作用的研究，包括干细胞相关研究，使得这项研究对于理解人类健康和人类发展特别重要。

DESCRIPTION Abstract: The control of metabolic pathways and mitochondrial activity and biogenesis during development will be explored using early mouse embryo and the embryonic stem cells derived from them as a model. This proposal is based on the importance of metabolic activity to human health and disorders and the relative lack of data on the mechanisms that control transition between various modes of metabolic activity during phases of development. Nuclear and mitochondrial activities constantly modulate each other, and the relationship between signal transduction pathways commonly studied during development, cancer and stem cell maintenance and metabolic pathways such as oxidative phosphorylation, glycolysis, mitochondrial biosynthesis and nutrient sensing will be explored. The techniques involved will require in vivo tagging of genes that are relevant to metabolism, then studying progression of metabolic gene activity during very early stages of mouse development. This will be followed by isolation of ES cells from these embryos, and through perturbation of various signaling pathways, the effects on their metabolic status will be identified. The overarching goal of this endeavor is to understand the molecular mechanisms underlying the developmental control of a Warburg effect -like transition between oxidative and glycolytic activity; and also to fully understand the nature of cross talk between the nucleus and the mitochondrion during mammalian development. This model is of relevance to studies on human stem cell biology and cancer. Public Health Relevance: This proposal is relevant to public health from many different angles. Metabolic disorders are of great significance and their study comprises the core of this proposal. However, it is the study of the interactions of metabolic pathways with those that have been linked to cancer and developmental defects, including stem cell related studies, is what makes this study particularly important for understanding human health a