Carotid Body Chemoreception: Mechanism & Development

颈动脉体化学感受：机制

• 批准号: 6890316
• 负责人: DAVID F. DONNELLY
• 金额: $ 32.7万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-05 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6890316
• 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; 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

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）：心脏呼吸系统的主要缺氧传感器是颈动脉体，它在出生时相对不敏感，并且在生命的前1-2周中成熟。尽管趋化转导的机制仍然晦涩难懂，但肾小球细胞，分泌细胞上的分泌细胞以及神经末端的分泌细胞以及神经末端本身似乎形成了关键的化学感受器。当前的模型表明，缺氧导致兴奋性发射机的释放，但是对所谓的兴奋性发射器的识别已证明难以捉摸，我们先前的结果以及其他实验室的结果表明，Glomus细胞分泌与传入神经活性之间存在分离。拟议的工作概述了了解转导机制的两个步骤：首先，要了解峰值产生的机理，其次是了解如何通过缺氧控制发电过程。为了第一个目的，我们证明：i）尖峰生成过程对靶向Na+通道的外部Na+扰动或药物高度敏感，ii）化学感受器传入神经元表达有限且一致的Na+通道谱，III）隔离，化学感受者的神经元能够产生自发性作用，从而产生了与该模式相关联的纽带。基于初步结果，我们的一般假设是神经终端是通过内源过程，特别是持续的Na+电流的动作电位产生的位点。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SOMA和神经末端的Na+通道同工型； 2）检查Na+电流扰动对针对快速Na+电流或同工型Navl.6和NAVL.8的快速Na+电流或损失（敲除）的药物后对缺氧和化学感受器活性的呼吸反应的后果； 3）检查了Na+通道的破坏不足/过表达对SOMA产生自发作用电位的能力的影响。预期的结果将提供或拒绝这种化学感受器转导的独特模型。如果得到支持，该模型应导致这些过程的药理靶向，以改善呼吸暂停和/或呼吸困难的治疗。