Oxygen (O2) is vital for the life of all aerobic animals. However, fine-tuned regulation of O2 levels is crucial since both shortage (hypoxia) and excess (via the production of reactive oxygen species, ROS) may be harmful. Indeed, both hypoxia and ROS may underlie the pathophysiology of many diseases such as atherosclerosis and Alzheimer’s. To understand how this fine-tuned O2 regulation is achieved at both the molecular and organismal levels my research proposal aims to explore the following integrated questions, using the nematode C. elegans as a model organism.
1) How do animal sense O2? What are the molecular sensors and how do they act together to fine-tune O2 responses?
2) How does O2 regulate food intake, and repress appetite in hypoxia?
3) How do animals survive and behaviorally adapt to hypoxia without HIF-1?
4) How hydrogen sulfide (H2S) regulates O2 responses and aging?
5) How do animals protect against mRNA oxidation damage?
I have focused my research on the globins. GLB-5 is a C. elegans hexacoordinated globin that regulates foraging behavior in response to subtle changes in O2 concentration. Like neuroglobin and cytoglobin in our brain, GLB-5 is expressed in neurons. Recently I discovered that GLB-5 regulates the re-adaptation of animals to 21% O2 after hypoxia. To understand how GLB-5 regulates hypoxia-reoxygenation responses I made a mutagenesis screen and isolated four classes of GLB-5 suppressors, and mapped them using single-nucleotide polymorphisms (SNP’s) to about a 1 Mbp genomic interval. Using a novel non-PCR based libraries preparation and Next Generation whole-genome sequencing, I have already sequenced four independent mutations and cloned one of the GLB-5 suppressors. In the future, I intend to clone more suppressor genes, and use this methodology in other parts of my project. By doing so, I aim to understand O2 homeostasis regulation at all levels; from the molecular signaling network to the physiology and behavior of the whole animal.
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