Oxygen deprivation generates a rise in mitochondrial-derived reactive oxygen species (mtROS). Over time, these mtROS can have a cumulative impact, with superoxide and its more reactive by-products inducing cellular damage. It is thus no surprise that hypoxia is a core element in the pathogenesis of many degenerative diseases, including chronic kidney disease and rheumatoid arthritis. Among the cellular responses to hypoxia, is the stabilization/accumulation of hypoxia-inducible factor-1? (HIF-1?). HIF-1? orchestrates a wide-ranging transcriptional adaptation program that includes shifting cellular metabolic strategy toward glycolytic energy production. The influence of HIF-1-mediated transcription is profound;unregulated activity of this pathway can trigger the progression of numerous forms of human cancers. Our preliminary data have demonstrated that HIF-1? also forms a complex with the orphan nuclear receptor (NR) estrogen receptor-related receptor (ERR) and that this association is required for a complete hypoxic response. Moreover, our data indicate that ERR is an essential regulator of carbohydrate metabolism. While it is evident that ERRs participate in HIF-1?-mediated transcription, the extent that these factors coordinate transcriptional responses remains unknown. The overarching objective of this proposal is to establish a foundation for understanding the physiologic significance of the HIF-1?/ERR complex. Toward this end, we will use the fruit fly, Drosophila melanogaster, as a simple model to delineate HIF-1/ERR-mediated events, employing both biochemical and genetic approaches. Flies have a robust hypoxic response that is mediated by Sima, the Drosophila ortholog of HIF-1?. Furthermore, Drosophila maintain a single, highly conserved err gene. We hypothesize that ERR associates with Sima under hypoxic conditions and that together, coordinately regulate genes that act to minimize the effects of oxidative stress. The rationale for the proposed research is that a greater understanding of the transcriptional pathways responsive to oxygen tension and cellular metabolic status will lead to new strategies that target these pathways for the management of conditions where oxidative stress is central to the etiology. PUBLIC HEALTH RELEVANCE: Insufficient response to oxidative toxicity is a central theme in degenerative disorders and a primary cause of aging, while unregulated activity of the adaptive response to low oxygen conditions is prevalent in many forms of human cancers. This proposed research will use Drosophila melanogaster to investigate the role the ERR nuclear receptor has in altering metabolism and transcription in response to oxygen availability.