Vascular Biology of Hydrogen Sulfide

硫化氢（H2S）长期以来被认为是一种有毒气体，最近在哺乳动物中被证明是一种神经递质和局部信号分子。该实验室最近的工作（NSF IBN-0235223）表明，H2S影响所有脊椎动物的心血管功能，这也导致了一个新的假设，即H2S是迄今为止难以捉摸的氧气“传感器”，在全身血管中产生缺氧松弛和肺血管中的缺氧收缩。该项目将研究H2S如何介导血管缺氧反应，以及该信号如何转导为收缩或松弛。它还将确定H2S在原始脊椎动物一般心血管功能中的作用。对单个平滑肌细胞的电生理研究，对分离血管的生化和生物物理研究，以及对未麻醉动物的完整心血管测量，将在从原始盲鳗到哺乳动物的各种脊椎动物上进行。这些研究将首次全面研究H2S是血管中氧气“感应”的关键成分的新假设，并将确定H2S在脊椎动物心血管系统中的系统发育起源和影响。通过解决长期存在的血管氧传感难题，这些结果将对所有脊椎动物生理学产生广泛的影响，并将为研究H2S在脊椎动物心血管系统中的综合作用提供一个进化窗口。这项工作也与环境生物学有关，因为H2S通常是工业和农业活动的副产品，它可能会使水生脊椎动物衰弱。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。

Long known as a toxic gas, hydrogen sulfide (H2S) has recently been shown in mammals to serve as a neurotransmitter and local signaling molecule. Recent work in this laboratory (NSF IBN-0235223) suggested that H2S impacts cardiovascular function in all vertebrates and it also led to the novel hypothesis that H2S is the heretofore elusive oxygen "sensor" producing hypoxic relaxation in systemic vessels and hypoxic constriction in pulmonary vessels. This project will examine how H2S mediates hypoxic responses in blood vessels and how this signal is transduced into contraction or relaxation. It will also determine the role of H2S in general cardiovascular function in primitive vertebrates. Electrophysiological studies on single smooth muscle cells, biochemical and biophysical studies of isolated blood vessels, and complete cardiovascular measurements on unanesthetized animals will be performed on a variety of vertebrates, from primitive hagfish to mammals. These studies will provide the first comprehensive investigation of the novel hypothesis that H2S is the key component in oxygen "sensing" in blood vessels and they will identify the phylogenetic origin and impact of H2S in the vertebrate cardiovascular system. The results will have broad implications for all of vertebrate physiology by resolving the long-standing conundrum of vascular oxygen sensing and they will provide an evolutionary window into the integrative role of H2S in the vertebrate cardiovascular system. This work is also relevant to environmental biology because H2S is often a byproduct of industrial and agricultural activity and it is potentially debilitating to aquatic vertebrates. In addition, this project will support the education of the next generation of "broad spectrum" comparative physiologists as it will provide an integrative training program from molecular biology to whole-animal physiology.