Carotid Body Chemoreception: Mechanism & Development

颈动脉体化学感受:机制

基本信息

  • 批准号:
    6890316
  • 负责人:
  • 金额:
    $ 32.7万
  • 依托单位:
  • 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 2007-04-30
  • 项目状态:
    已结题

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,颈动脉体在出生时相对不敏感,在出生后1-2周内逐渐成熟。虽然化学转导的机制尚不清楚,但血管球细胞、与传入神经末梢相对的分泌细胞以及神经末梢本身似乎构成了关键的化学接受单元。目前的模型表明,缺氧导致兴奋性递质的释放,但对所谓的兴奋性递质的识别已被证明是难以捉摸的,我们之前的结果以及其他实验室的结果表明,球囊细胞分泌和传入神经活动之间存在分离。这项工作概述了理解转导机制的两个步骤:首先,了解尖峰产生的机制,其次,了解产生过程是如何受缺氧控制的。为了实现第一个目标,我们证明:1)脉冲产生过程对外部Na+扰动或靶向Na+通道的药物高度敏感;2)化学受体传入神经元表达有限且一致的Na+通道轮廓;3)分离的化学受体传入神经元能够产生与传入神经末梢产生的模式相似的自发动作电位。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产生动作电位的部位,特别是持续的Na+电流。拟开展的工作:1)利用RT-PCR和免疫细胞化学技术鉴定化学受体神经元体细胞和神经末梢的Na+通道亚型;2)研究Na+电流扰动对缺氧呼吸反应和化疗受体活性的影响,这些药物靶向快速Na+电流或丢失(敲除)同种异构体Navl.6和Navl.8;3)研究Na+通道过表达/过表达中断对胞体自发动作电位产生能力的影响。预期的结果将提供接受或拒绝这种独特的化学受体转导模型。如果得到支持,该模型将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。

项目成果

期刊论文数量(0)
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会议论文数量(0)
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DAVID F. DONNELLY其他文献

DAVID F. DONNELLY的其他文献

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{{ truncateString('DAVID F. DONNELLY', 18)}}的其他基金

Mechanism of perinatal-hyperoxic suppression of chemoreceptor function
围产期高氧抑制化学感受器功能的机制
  • 批准号:
    7637463
  • 财政年份:
    2007
  • 资助金额:
    $ 32.7万
  • 项目类别:
Mechanism of perinatal-hyperoxic suppression of chemoreceptor function
围产期高氧抑制化学感受器功能的机制
  • 批准号:
    7877740
  • 财政年份:
    2007
  • 资助金额:
    $ 32.7万
  • 项目类别:
Mechanism of perinatal-hyperoxic suppression of chemoreceptor function
围产期高氧抑制化学感受器功能的机制
  • 批准号:
    7463657
  • 财政年份:
    2007
  • 资助金额:
    $ 32.7万
  • 项目类别:
Mechanism of perinatal-hyperoxic suppression of chemoreceptor function
围产期高氧抑制化学感受器功能的机制
  • 批准号:
    7319148
  • 财政年份:
    2007
  • 资助金额:
    $ 32.7万
  • 项目类别:
Carotid Body Chemoreception: Mechanism & Development
颈动脉体化学感受:机制
  • 批准号:
    6641064
  • 财政年份:
    2003
  • 资助金额:
    $ 32.7万
  • 项目类别:
Carotid Body Chemoreception: Mechanism & Development
颈动脉体化学感受:机制
  • 批准号:
    6744725
  • 财政年份:
    2003
  • 资助金额:
    $ 32.7万
  • 项目类别:
Carotid Body Chemoreception: Mechanism & Development
颈动脉体化学感受:机制
  • 批准号:
    7056790
  • 财政年份:
    2003
  • 资助金额:
    $ 32.7万
  • 项目类别:
STIMULUS SECRETION COUPLING IN CAROTID BODY GLOMUS CELLS
颈动脉体球细胞的刺激分泌耦合
  • 批准号:
    2231668
  • 财政年份:
    1994
  • 资助金额:
    $ 32.7万
  • 项目类别:
STIMULUS SECRETION COUPLING IN CAROTID BODY GLOMUS CELLS
颈动脉体球细胞的刺激分泌耦合
  • 批准号:
    2231666
  • 财政年份:
    1994
  • 资助金额:
    $ 32.7万
  • 项目类别:
STIMULUS SECRETION COUPLING IN CAROTID BODY GLOMUS CELLS
颈动脉体球细胞的刺激分泌耦合
  • 批准号:
    2029294
  • 财政年份:
    1994
  • 资助金额:
    $ 32.7万
  • 项目类别:

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  • 批准号:
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  • 财政年份:
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