Organisms eat to live, and diet provides material for growth and maintenance. However, complex webs of nutrient-responsive signaling pathways ensure that nutrients are properly allocated and utilized to support cellular processes such as proliferation and differentiation, commensurate with the demands of developmental stage and organismal needs. We know that signaling in response to diet is key to functional provisioning of dietary components, since signaling pathways can be manipulated to overcome nutritional deficits that would otherwise impair these processes. However, despite the fundamental nature of diet and metabolic signaling, the identity of key dietary factors, how they trigger particular signaling pathways in vivo, and how they operate within organismal metabolism to regulate cell behavior are poorly understood. We are addressing this gap using C. elegans germline progenitor cells as a model system. Germ cells are exquisitely sensitive to diet, making them an ideal model. Stem and progenitor cells are important targets of diet-based signaling, since they must continuously maintain tissues and organs under changing conditions. C. elegans offers experimental advantages including facile genetic and dietary manipulation. In addition, the C. elegans laboratory diet, E. coli, is itself a genetically tractable organism. Using complementary candidate and unbiased approaches, this project will identify dietary components that drive progenitor accumulation. Dietary cues will be linked to specific known (insulin, TGF-beta and TOR) or yet-to-be-implicated signaling pathways and cellular response mechanisms. The project will also address how robust accumulation of germline progenitors, in response to parental diet, impacts subsequent generations. Due to the highly conserved nature of metabolism and nutrient-reponsive signaling across evolutionarily divergent organisms, our studies will contribute to the understanding of fundamental mechanisms that maintain proliferating pools of cells, with possible implications in humans for fertility, development, degenerative diseases, cancer, stem cell biology, and parasite biology.
This project will identify dietary components and how they act via signaling pathways to regulate cell proliferation and differentiation in the context of an intact animal. Due to the highly conserved nature of metabolic signaling, our studies will contribute to understanding of fundamental mechanisms that maintain proliferating pools of cells, with possible implications for human fertility, development, degenerative diseases, cancer, stem cell biology, and parasite biology.