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

多细胞生物体显示各种感官受体，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是必不可少的，特殊的O2-受体有助于维持身体组织的最佳氧气供应，以满足单个细胞的新陈代谢需求。这些O2-受体中的一些也能够检测到CO2/H+。O2和CO2/H+传感的细胞/分子机制还不是很清楚。我的实验室对了解这些机制以及它们在脊椎动物中的进化很感兴趣。到目前为止，我们的大部分工作都集中在呼吸空气的哺乳动物身上，在这些哺乳动物中，特定的化学感受器(如颈动脉小体和肾上腺)含有被赋予检测低O2(低氧)和高CO2/H+的特殊机制的细胞。最基本的机制可能首先出现在呼吸水的动物中，例如鱼类，在过去几年中，在NSERC的支持下，我的实验室对斑马鱼鳃模型中的氧气感知和神经模式的机制进行了一系列重要的开创性研究。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氧修饰，以及神经纤维如何投射到几种水生脊椎动物的这些细胞中。在这一续展申请中，我们将扩展我们的比较分析，以包括两栖动物(非洲爪哇)鳃的NECS。我们的工作假设是，在哺乳动物中被广泛研究的O2和CO2/H+感知的基本机制，首先出现在水呼吸动物中，并在脊椎动物中保守。我们将验证这一观点，即K+通道活性的调节在这些感知途径中是一个高度保守的机制，以及最近提出的气体信号分子，即硫化氢(H2S)，可能在缺氧感知中发挥更普遍的作用。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O2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.