Hydrogen Sulfide: A Primal Vascular Oxygen Sensor

外部或内部来源的氧气不足(缺氧)对所有动物都是一个潜在的和反复出现的威胁。脊椎动物呼吸道和血管中复杂而专门的“氧气感应”细胞已经被开发出来，以确保氧气输送到身体以及分配到每一个组织。然而，目前还不知道这些细胞是如何感知缺氧的，或者这个信号是如何启动后续的生理反应的。通过先前NSF(iOS 064-1436)的支持，PI的实验室已经为一种基于硫化氢(H2S)细胞内代谢的新氧传感机制提供了证据。在这个模型中，硫化氢由细胞持续产生，并在氧气存在时迅速氧化(失活)。然而，在没有氧气的情况下，硫化氢会积累，这会引发一连串的生理反应。本项目将研究缺氧和硫化氢对离体血管和组织的影响，量化氧依赖的硫化氢代谢的生物化学，并确定硫化氢产生和失活的细胞内位置。具有广泛进化、环境和生理属性的脊椎动物将被研究，包括耐缺氧和最原始的脊椎动物(七目鳗和七鳃鳗)、爬行动物(鳄鱼和海龟)、耐缺氧潜水哺乳动物(海豹和海狮)以及耐缺氧鱼(鲑鱼)和哺乳动物(老鼠和牛)。这些研究将检验硫化氢介导的氧气感应是否是所有脊椎动物的基本和普遍属性，这些信息对于理解缺氧的病理生理学将是非常宝贵的，无论是环境、组织还是细胞内的起源。此外，该项目还将支持下一代“广谱”比较生理学家的教育，因为它将提供从分子生物学到全动物生理学的综合培训计划。

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.