Carotid Body Chemoreception: Mechanism & Development

颈动脉体化学感受：机制

基本信息

批准号：
7056790
负责人：
DAVID F. DONNELLY
金额：
$ 31.93万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-05-05 至 2007-10-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7056790
关键词：
action potentials biological signal transduction carotid body developmental neurobiology hypoxia ion channel blocker laboratory mouse laboratory rat nerve endings plethysmography protein isoforms single cell analysis sodium channel soma tissue /cell culture

项目摘要

DESCRIPTION (provided by applicant): The primary hypoxia sensor of the cardio-respiratory system is the carotid body, which is relatively insensitive at birth and matures over the first 1-2 weeks of life. Although the mechanism of chemotransduction remains obscure, glomus cells, secretory cells apposed to the afferent nerve endings, as well as the nerve endings themselves appear to form the critical chemoreceptive unit. Current models propose that hypoxia causes release of an excitatory transmitter, but identification of the purported excitatory transmitter has proven elusive and our previous results, as well those of other laboratories, demonstrate a dissociation between glomus cell secretion and afferent nerve activity. The proposed work outlines two steps in understanding the mechanism of transduction: firstly, to understand the mechanism of spike generation and secondly, to understand how the generation process is controlled by hypoxia. Towards the first aim, we demonstrate: i) that the spike generation process is highly sensitive to external Na+ perturbation or drugs which target Na+ channels, ii) chemoreceptor afferent neurons express a limited and consistent Na+ channel profile and iii) isolated, chemoreceptor afferent neurons are able to generate spontaneous action potentials which resemble the pattern as generated by the afferent nerve ending. Based on the preliminary results, our general hypothesis is that the nerve terminals are the site of action potential generation through an endogenous process, specifically, a persistent Na+ current. The proposed work: 1) uses RT-PCR and immunocytochemistry to identify Na+ channel isoforms at the soma and nerve terminals of chemoreceptor neurons; 2) examines the consequences of Na+ current perturbations on the respiratory response to hypoxia and chemoreceptor activity following drugs which target fast Na+ currents or loss (knockout) of isoforms Navl.6 and Navl.8; 3) examines the effects of disruption of Na+ channel underexpression/overexpression on the ability of the soma to generate spontaneous action potentials. The anticipated results will provide acceptance or rejection of this unique model of chemoreceptor transduction. If supported, the model should lead to a pharmacologic targeting of these processes for the improved treatment of apnea and/or dyspnea.

描述（由申请人提供）：心肺系统的主要缺氧传感器是颈动脉体，其在出生时相对不敏感，并在生命的前 1-2 周内成熟。尽管化学转导的机制仍然不清楚，但血管球细胞、传入神经末梢的分泌细胞以及神经末梢本身似乎形成了关键的化学感受单位。目前的模型提出，缺氧会导致兴奋性递质的释放，但事实证明，所谓的兴奋性递质的识别是难以捉摸的，我们之前的结果以及其他实验室的结果表明，血管球细胞分泌与传入神经活动之间存在分离。拟议的工作概述了理解转导机制的两个步骤：首先，了解尖峰生成的机制，其次，了解缺氧如何控制生成过程。为了实现第一个目标，我们证明：i）尖峰生成过程对外部 Na + 扰动或针对 Na + 通道的药物高度敏感，ii）化学感受器传入神经元表达有限且一致的 Na + 通道配置文件，以及 iii）分离的化学感受器传入神经元能够产生类似于传入神经末梢产生的模式的自发动作电位。根据初步结果，我们的一般假设是神经末梢是通过内源性过程（特别是持续的 Na+ 电流）产生动作电位的部位。拟议的工作：1）使用RT-PCR和免疫细胞化学来鉴定化学感受器神经元的体细胞和神经末梢的Na+通道亚型； 2)检查Na+电流扰动对缺氧呼吸反应和化学感受器活性的影响，这些药物针对快速Na+电流或异构体Navl.6和Navl.8的损失（敲除）； 3) 检查Na+通道低表达/过度表达的破坏对体体产生自发动作电位的能力的影响。预期结果将提供对这种独特的化学感受器转导模型的接受或拒绝。如果得到支持，该模型应该能够针对这些过程进行药理学靶向，以改善呼吸暂停和/或呼吸困难的治疗。