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

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，并在出生后的前1-2周内成熟。虽然化学传导的机制仍然不清楚，但与传入神经末梢并列的血管球细胞、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，缺氧导致兴奋性递质的释放，但所谓的兴奋性递质的识别已被证明是难以捉摸的，我们以前的结果，以及其他实验室的结果，表明球细胞分泌和传入神经活动之间的解离。拟议的工作概述了两个步骤，在理解转导机制：首先，了解穗产生的机制，其次，了解如何生成过程是由缺氧控制。朝向第一个目标，我们证明：i）尖峰生成过程对外部Na+扰动或靶向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+通道轮廓，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。基于初步结果，我们的一般假设是，神经末梢是通过内源性过程产生动作电位的部位，具体地说，是持续的Na+电流。拟议的工作：1）利用RT-PCR和免疫细胞化学鉴定化学感受器神经元索马和神经末梢的Na+通道亚型; 2）检查Na+电流扰动对缺氧呼吸反应和靶向快速Na+电流或损失的药物后化学感受器活性的影响（敲除）同种型Navl.6和Navl.8; 3）检查Na+通道低表达/过表达的破坏对索马产生自发动作电位的能力的影响。预期的结果将提供接受或拒绝这种独特的模型的化学感受器转导。如果得到支持，该模型应导致这些过程的药理学靶向，以改善呼吸暂停和/或呼吸困难的治疗。