The hexosamine biosynthesis pathway in metabolism and cell fate

PROJECT SUMMARY Cell fate is determined by a number of factors including genetics, cellular signals and availability of nutrients. How cells process these numerous inputs to produce a specific output, such as cell differentiation or proliferation remains poorly understood. Our project will address how cells process these inputs following the principle of “supply and demand.” During early T cell development, the synthesis of a diverse repertoire of T cell receptors defines a robust immune system that will allow recognition of various pathogens, while tolerant to self-peptides. The synthesis of a diverse repertoire requires abundant nucleotides and hexosamines for proper synthesis and folding. Our studies will elucidate how the de novo hexosamine biosynthesis pathway reprogram metabolism via regulation of mTOR signaling and pyrimidine metabolism to generate a diverse TCR repertoire. As we gain better understanding of how these pathways are reprogrammed to balance nutrient supply with cellular demand, we hope to develop better strategies for dietary manipulation that can potentially enhance the functions of the immune system.