RUI: Comparative Hypoxic Chemosensitivity of Two Rat Strains

动物对低氧环境的反应是增加呼吸。这种呼吸的增加是由被称为颈动脉小体的结构中的氧气敏感细胞刺激的。关于颈动脉体细胞如何将血液中低氧水平(低氧)的信号转化为神经信号，从而导致呼吸增加，有许多理论，但哪种理论是正确的仍未解决。血液中的氧气以存在于红细胞中的血红蛋白的形式存在。血红蛋白是一种所谓的‘血红素’蛋白，在身体的其他细胞中也有其他的血红素蛋白。关于颈动脉小体细胞如何感知氧气水平变化的理论之一是通过一种可以在细胞内或细胞膜上与氧结合的血红素蛋白。对几种哺乳动物、鸟类甚至一些爬行动物的比较研究表明，血红蛋白对氧气的亲和力，或血红蛋白与氧气结合的难易程度，与刺激呼吸增加所需的血液中氧气的减少量之间存在很好的相关性。这一观察的机制可能是血液中b型血红素蛋白结合氧的特征与颈动脉小体氧敏感细胞中b型血红素蛋白结合氧的特征相匹配或共同。如果是这样的话，这一机制可能不仅有助于阐明颈动脉小体是如何工作的，而且还可能有助于阐明呼吸控制是如何进化到与血液的氧气运输特性很好地匹配的。为了进一步探索这一概念，该项目将研究两种品系的大鼠，它们对缺氧或缺氧表现出不同的呼吸和代谢反应。将确定它们的血红蛋白结合特性是否不同，并将测量它们的颈动脉体对低氧的反应特征或敏感性，以确定整个动物在呼吸和代谢方面的低氧敏感度差异是否与颈动脉体低氧敏感度的差异有关。如果它们是相关的，那么未来将对颈动脉小体和氧敏感离子通道中的血红素蛋白进行比较研究。如果不是，那么关于控制不同低氧敏感性的机制的替代假设将被寻求。

Animals respond to environments that are low in oxygen by increasing their breathing. This increase in breathing is stimulated by oxygen sensitive cells in a structure called the carotid body. There are a number of theories about how the carotid body cells can transduce the signal of low oxygen levels (hypoxia) in the blood into nerve signals to the brain that cause the increase in breathing, but which theory is correct remains unresolved. Oxygen is carried in the blood on hemoglobin that is present in red blood cells. Hemoglobin is a so-called 'heme'-protein and there are other heme-proteins in other cells in the body. One of the theories about how carotid body cells sense changes in oxygen levels is via a heme-protein that can bind oxygen either inside the cell or at its membrane. Comparative studies of several species of mammals, birds and even some reptiles have demonstrated a good correlation between the affinity of hemoglobin for oxygen, or the ease with which hemoglobin binds oxygen, and the amount of decline in oxygen in the blood required to stimulate an increase in breathing. The mechanism underlying this observation may be a matching or commonality of oxygen binding characteristics of the b-type heme protein binding oxygen in the blood and a b-type heme protein binding oxygen in the oxygen sensitive cells of the carotid bodies. If this is the case, the mechanism may help elucidate not only how the carotid bodies work but how the control of breathing has evolved to be well matched to the oxygen transport properties of the blood. To explore this concept further this project will investigate two strains of rats that exhibit different breathing and metabolic responses to reduced oxygen or hypoxia. The binding characteristics of their hemoglobin will be determined to see if they differ, and the response characteristics, or sensitivity, of their carotid bodies to hypoxia will be measured to determine whether or not the differences in hypoxic sensitivity of the whole animal, in terms of breathing and metabolism, can be related to differences in the hypoxic sensitivity of the carotid body. If they are related, then future comparative studies of heme-proteins in the carotid bodies and oxygen sensitive ion channels will be conducted. If not, then alternative hypotheses about the mechanisms controlling the different hypoxic sensitivities will be pursued.