Developmental Control of Metabolism

描述 摘要： 将以小鼠早期胚胎及其衍生的胚胎干细胞为模型，探索发育过程中代谢途径、线粒体活性和生物发生的控制。这一建议是基于代谢活动对人类健康和疾病的重要性，以及在发育阶段控制不同代谢活动模式之间转换的机制的相对缺乏的数据。核和线粒体活动不断地相互调节，并将探索在发育、癌症和干细胞维持过程中通常研究的信号转导途径与氧化磷酸化、糖酵解、线粒体生物合成和营养感知等代谢途径之间的关系。所涉及的技术将需要在体内标记与新陈代谢相关的基因，然后研究小鼠发育早期代谢基因活动的进展。随后将从这些胚胎中分离出ES细胞，通过干扰各种信号通路，将确定对其代谢状态的影响。这项工作的首要目标是了解氧化和糖酵解活性之间类似Warburg效应的转变的发育控制的分子机制，以及充分了解哺乳动物发育过程中细胞核和线粒体之间的串扰的性质。该模型对人类干细胞生物学和癌症的研究具有重要意义。 公共卫生相关性： 这项建议从许多不同的角度与公共卫生有关。代谢紊乱具有重要意义，他们的研究构成了这一提议的核心。然而，正是代谢途径与那些与癌症和发育缺陷有关的代谢途径的相互作用的研究，包括与干细胞相关的研究，使这项研究对理解人类健康特别重要。

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