Insufficient oxygen (hypoxia) of external or internal origin is a potential and recurring threat to all animals. Complex and specialized "oxygen sensing" cells in vertebrate airways and blood vessels have been developed to ensure oxygen delivery to the body as well as its distribution to every tissue. It is not known, however, how these cells sense hypoxia or how this signal initiates subsequent physiological responses. Through previous support from the NSF (IOS 064-1436) the PI's laboratory has provided evidence for a new mechanism of oxygen sensing based on intracellular metabolism of hydrogen sulfide (H2S). In this model, H2S is continuously produced by cells and rapidly oxidized (inactivated) when oxygen is present. However, in the absence of oxygen, H2S accumulates and this initiates a cascade of physiological responses. This project will examine the effects of hypoxia and H2S on isolated vessels and tissues, quantify the biochemistry of oxygen dependent H2S metabolism, and identify the intracellular sites of H2S production and inactivation. Vertebrates with wide-ranging evolutionary, environmental, and physiological attributes will be examined including the hypoxia tolerant and most primitive vertebrates (hagfish and lamprey), reptiles (alligators and turtles), hypoxia tolerant diving mammals (seals and sea lions) and hypoxia intolerant fish (trout) and mammals (rats and cows).
These studies will examine whether H2S-mediated oxygen sensing is a fundamental and universal attribute of all vertebrates and this information will be invaluable in understanding the pathophysiology of hypoxia, be it environmental, tissue, or intracellular in origin. In addition, this project will support the education of the next generation of "broad spectrum" comparative physiologists since it will provide an integrative training program from molecular biology to whole-animal physiology.
