Mitochondrial-derived reactive oxygen species (ROS) are a harmful by-product of oxygen deprivation. Cell damage from ROS exposure can be irreversible, and chronically high levels of ROS are a characteristic of the pathogenesis of many degenerative diseases and cancers. In order to mitigate the effects of ROS in hypoxic environments, oxygen-sensitive pathways have evolved that initiate adaptive responses, including a marked shift in metabolic strategy toward lactate production. These metabolic changes are supported by a wide-ranging transcriptional response to hypoxia. Many of the transcriptional responses proceed through the actions of the hypoxia-inducible factor-1 (HIF-1) pathway, but emerging evidence suggests that non-HIF-mediated pathways are also prominent in the responses and provide essential adaptive support. The regulators and upstream mediators for the non-HIF-mediated responses are not well understood, or not known at all. This project seeks to use Drosophila genetics as a tool to uncover these factors using hypoxia-sensitive sensor animals coupled to an unbiased genetic screen of the third chromosome.
The complex transcriptional and metabolic events that support successful adaptation responses in low oxygen are not well understood, yet these processes are essential factors in many diseases, including cancers and heart disease. This proposed research uses Drosophila melanogaster as a tool to identity non-HIF-mediated factors that facilitate adaptive responses in hypoxia.
