Signaling and Metabolic Regulation of Nucleotide Metabolism and Cell Growth

PROJECT SUMMARY Nucleotides serve as pivotal bioenergetic molecules vital for diverse cellular processes, encompassing RNA and DNA synthesis, glycosylation, phospholipid metabolism, energy production, signaling, and cytoskeleton function. During the past decade, my independent research has led to fundamental insights into the molecular mechanisms that govern the metabolic pathways, enabling cells to grow and proliferate. My laboratory has made significant discoveries by molecularly connecting the pro-proliferative signaling pathways to nucleotide metabolism. We have achieved landmark discoveries by precisely delineating the molecular regulation of de novo purine synthesis downstream of the ERK signaling pathway, elucidating the effects of mTORC1 signaling on the methionine cycle and RNA methylation, and demonstrating the pivotal role of environmental bicarbonate in fueling de novo nucleotide synthesis in response to mTORC1 activation. Recently, our findings have not only expanded our understanding of metabolic function but also reshaped the biochemical landscape. We have overturned conventional wisdom by revealing the indispensable role of pyrimidine nucleotides in supporting vitamin B1 metabolism and mitochondrial pyruvate oxidation and Krebs cycle function. These revelations hold profound implications, not only for our comprehension of metabolic physiology but also for the development of innovative drug strategies. The success of our efforts has been underpinned by the support of two NIGMS- funded R01 grants, serving as the lifeblood of our research pursuits. My lab has thrived in answering fundamental questions regarding cellular metabolism regulation and uncovering novel metabolic functions for purine and pyrimidine nucleotides. This proposal embodies the ethos of the MIRA funding scheme, empowering researchers to pursue ambitious science and delve into higher-risk endeavors. Through MIRA funding, we aim to uncover metabolic connections between the nucleotide synthesis pathways and metabolites, identify the molecular mechanisms of nucleotide sensing in human cells, and expand the horizons of our research endeavors. The stability and flexibility inherent in MIRA funding will enable us to propel scientific discovery forward, forging new knowledge in the realm of signaling and cellular metabolism and advancing our quest for innovations.