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Abstract

Cells, tissues, and organisms encounter many harmful environmental stresses, and the ability to mount specific stress responses is critical for their function and survival. Stress occurs in many pathological states and is therefore of great biomedical relevance, both as cause or contributor to diseases and as potential therapeutic targets. In my thesis, three stresses were studied that occur in both healthy eukaryotes and in disease states. The pathways that regulate the responses to oxidative stress, hypoxia, and starvation are evolutionarily conserved from the nematode worm Caenorhabditis elegans to humans and involve master regulators of gene expression that are critical in the control of cellular responses to, and the defence against these stresses. Hypoxia occurs when oxygen levels become too low for normal physiological functions, and the response to hypoxia requires the master regulator HIF. Oxidative stress occurs when ROS, by-products of aerobic respiration, accumulate within the cell to toxic levels, and the response to elevated ROS typically requires the master regulator SKN-1/Nrf2. Starvation is the short or long-term absence of nutrients, and the response to starvation requires the master regulator HLH-30/TFEB. Although the responses controlled by these master regulators are considered the principal pathways, evidence for parallel programs exist. Here, I describe stress response pathways controlled by C. elegans NHR-49, an orthologue of mammalian PPARα, which is required to survive tBOOH oxidative stress and starvation. I show that nhr-49 is required for animal survival in hypoxia in parallel with hif-1. RNA-seq analysis shows that in hypoxia nhr-49 regulates a set of genes that are hif-1-independent, including autophagy genes that promote hypoxia survival. In addition, I performed reverse genetic screens to identify potential regulators of NHR-49 in stress response, uncovering 37 candidate kinases, transcription factors, and co-factors which may regulate NHR-49 controlled responses to tBOOH, hypoxia, and starvation. Follow up with one candidate gene, the kinase hpk-1, verified that it acts with NHR-49 to promote worm survival to hypoxia and oxidative stress, potentially working upstream of NHR-49 to activate it. Together, my experiments define new stress response pathways that act in parallel with the SKN-1, HIF-1, and HLH-30 mediated stress responses.