The role of nuclear receptors in Drosophila metabolism and development.Education
- B.A., 1996, Baylor University
- Ph.D., 2002, University of Texas Southwestern Medical Center
- University of Utah School of Medicine
Nuclear receptors are a superfamily of highly conserved transcription factors that bind small lipophilic compounds such as fatty acids, steroids, and bile acids. Upon binding to these ligands, nuclear receptors facilitate expression of genes involved in diverse processes, including development, maturation, reproduction, and metabolic homeostasis. Our long-term goal is to elucidate the cellular and organism-wide role(s) of nuclear receptors and their partner proteins. Accordingly, we use the fruit fly, /Drosophila melanogaster/, as a model organism to delineate fundamental aspects of nuclear receptor-mediated transcription pathways under varying developmental and environmental conditions. Our current studies focus on the transcriptional regulation of glycolytic pathways by the estrogen receptor-related receptor (ERR). Mounting evidence suggests that ERR significantly impacts nearly every aspect of carbohydrate metabolism. Moreover, we have recently discovered a direct link with ERR to the hypoxia-inducible factor-1a (HIF-1).
HIF-1 sits at the top of a transcriptional hierarchy that mediates a broad cellular adaptation program in response to oxygen deprivation. It has been estimated that 2-5% of all genes change their expression profile in a HIF-dependent manner when subjected to hypoxia; these changes often have a profound effect on cellular ‘character’ and decision-making. Among the processes most affected are the stimulation angiogenesis, erythropoiesis, and glycolysis. Importantly, ectopic and unregulated activity of the HIF-1 pathway occurs in many forms of human cancers, making HIF-1-mediated transcription an attractive target for cancer therapy. ERR’s unexpected role in the hypoxic response provides a new avenue by which the HIF-1 pathway may be targeted. In particular, we are interested in understanding the circumstances that dictate ERR collaboration with HIF-1 and how this pairing influences energy expenditure decisions.