Hydrogen Sulfide: A Primal Vascular Oxygen Sensor

外部或内部来源的氧气不足（缺氧）是对所有动物的潜在和反复威胁。脊椎动物气道和血管中的复杂和专门的“氧传感”细胞已经被开发出来，以确保氧气输送到身体以及氧气分配到每个组织。然而，目前尚不清楚这些细胞如何感知缺氧或这种信号如何引发随后的生理反应。通过之前NSF（IOS 064-1436）的支持，PI实验室为基于硫化氢（H2S）细胞内代谢的氧传感新机制提供了证据。在该模型中，H2S由细胞连续产生，并且在氧气存在时快速氧化（失活）。然而，在没有氧气的情况下，H2S积累，这引发了一系列生理反应。该项目将研究缺氧和H2S对离体血管和组织的影响，量化氧依赖性H2S代谢的生物化学，并确定H2S产生和失活的细胞内位点。将研究具有广泛进化、环境和生理属性的脊椎动物，包括耐缺氧和最原始的脊椎动物（盲鳗和七鳃鳗）、爬行动物（短吻鳄和海龟）、耐缺氧潜水哺乳动物（海豹和海狮）和耐缺氧鱼类（鳟鱼）和哺乳动物（大鼠和奶牛）。这些研究将检查H2S介导的氧传感是否是所有脊椎动物的基本和普遍属性，并且这些信息对于理解缺氧的病理生理学是非常宝贵的，无论是环境，组织还是细胞内起源。此外，该项目将支持下一代“广谱”比较生理学家的教育，因为它将提供从分子生物学到整体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.