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.
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 and disorder.
|Nagaraj, Raghavendra; Sharpley, Mark S; Chi, Fangtao et al. (2017) Nuclear Localization of Mitochondrial TCA Cycle Enzymes as a Critical Step in Mammalian Zygotic Genome Activation. Cell 168:210-223.e11|
|Isganaitis, Elvira; Jimenez-Chillaron, Jose; Woo, Melissa et al. (2009) Accelerated postnatal growth increases lipogenic gene expression and adipocyte size in low-birth weight mice. Diabetes 58:1192-200|