Comparative mechanisms of O2 and CO2/H+ chemoreception in vertebrates

多细胞生物显示出多种感觉受体，使它们能够感知环境刺激的变化，并做出对生存至关重要的适当反应。由于氧气（O2）对许多生物体的生存至关重要，因此专门的O2受体有助于维持身体组织的最佳氧气供应，以满足单个细胞的代谢需求。其中一些O2-受体也能够检测CO2/H+。O2和CO2/H+传感的细胞/分子机制尚未完全了解。我的实验室有兴趣了解这些机制，以及它们在脊椎动物中的进化。迄今为止，我们的大部分工作都集中在呼吸空气的哺乳动物，其中特定的化学感受器官（如颈动脉体和肾上腺）包含具有检测低O2（缺氧）和升高的CO2/H+的专门机制的细胞。基本的机制可能首先出现在水呼吸的动物，如鱼，并在NSERC的支持下，在过去的几年里，我的实验室进行了一系列重要的开拓性研究的机制O2传感和神经支配模式的斑马鱼鳃模型。我们研究了这些受体（即神经上皮细胞或NEC）中的特定离子通道蛋白如何被低O2修饰，以及神经纤维如何投射到几种水生脊椎动物中的这些细胞。在这个更新的应用程序中，我们将扩展我们的比较分析，包括NEC的两栖动物（非洲爪蟾）鳃。我们的工作假设是，O2和CO2/H+传感的基本机制，已被广泛研究的哺乳动物，首先出现在水呼吸和脊椎动物之间的保守。我们将测试的想法，K+通道活性的调节是一个高度保守的机制，在这些传感途径和最近提出的气体信号分子，即硫化氢（H2S），可能会发挥更普遍的作用，在缺氧传感。这项重要的研究有望深入了解动物（包括人类）如何感知和适应低氧和高CO2/H+条件，以及为什么不这样做会导致危及生命的情况。

Multicellular organisms display a variety of sensory receptors, which allow them to sense variations in environmental stimuli, and make appropriate responses crucial for survival. Since oxygen (O2) is essential for the survival of many organisms, specialized O2-receptors help maintain an optimal supply of oxygen to the body tissues so as to meet the metabolic needs of individual cells. Some of these O2-receptors are able to detect CO2/H+ as well. The cellular/molecular mechanisms of O2 and CO2/H+ sensing are not well understood. My laboratory is interested in understanding these mechanisms, as well as their evolution in vertebrates. Much of our work to date has focused on air-breathing mammals, where particular chemoreceptive organs (e.g. carotid body and adrenal gland) contain cells endowed with specialized mechanisms for detecting low O2 (hypoxia) and elevated CO2/H+. The basic mechanisms probably arose first in water-breathing animals, e.g. fish, and with the aid of NSERC support over the last several years my laboratory carried out an important series of pioneering studies on the mechanisms of O2 sensing and innervation patterns in the zebrafish gill model. We studied how specific ion channel proteins in these receptors (i.e. neuroepithelial cells or NECs) are modified by low O2, and how nerve fibers project to these cells in several aquatic vertebrates. In this renewal application we will extend our comparative analysis to include NECs of the amphibian (Xenopus) gill. Our working hypothesis is that the fundamental mechanisms of O2 and CO2/H+ sensing, that have been studied extensively in mammals, arose first in water-breathers and are conserved among the vertebrates. We will test the idea that regulation of K+ channel activity is a highly conserved mechanism in these sensing pathways and that the recently-proposed gaseous signaling molecule, i.e. hydrogen sulfide (H2S), may play a more general role in hypoxia-sensing. This important research is expected to yield insight into how animals (including humans) sense and adapt to low O2 and high CO2/H+ conditions, and why failure to do so leads to life-threatening situations.