权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Airway Sensory Neuroexcitability

气道感觉神经兴奋性

基本信息

批准号：
8513392
负责人：
Bradley Joel Undem
金额：
$ 38.64万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-02-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8513392
关键词：
Address Afferent Neurons Attention Biology Bladder Bronchial Spasm Burn injury C Fiber Coughing Disease Dyspnea Electrophysiology (science)Esthesia Family Future GDNF gene Ganglia Gastrointestinal tract structure Goals Grant Green Fluorescent Proteins Health Heart Imagery Inflammation Inflammation Mediators Inflammatory Knowledge Lead Location Lung Methods Mucous body substance NGFR Protein Nature Nerve Nerve Growth Factor Receptors Neural Crest Neurobiology Neuronal Plasticity Neurons Neurotrophic Tyrosine Kinase Receptor Type 2 Nociception Nodose Ganglion Pharyngeal structure Phenotype Physiology Play Reflex action Regulation Relative (related person)Respiratory System Respiratory tract structure Role Sensory Signs and Symptoms Sneezing Sodium Channel Spinal Ganglia Stimulus Symptoms Techniques Tetrodotoxin Time Tissues Vasodilation Virus Visceral afferent nerve base design in vivo insight neuronal cell body neurophysiology neurotrophic factor novel public health relevance receptor receptor expression research study respiratory selective expression somatosensory vector voltage

项目摘要

DESCRIPTION (provided by applicant): Activation of sensory C-fiber nerves in the airways can lead to coughing, sneezing, sensations of breathlessness, reflex mucus secretions and airway narrowing. These nerves play an important role in defending the airways from potentially damaging substances, but in inflammatory airway disease, their incessant activation may underlie many of the symptoms and much of the suffering associated the disorder. Since the classical studies by Coleridges and their colleagues in the 1970s and 80s, it has been recognized, at least at a descriptive level, that vagal C-fibers in the respiratory tract comprise at least two phenotypes, often referred to as "bronchial C-fibers" and "pulmonary C-fibers". The distinction based on the general location of the nerve terminals. We propose that it may be more useful to evaluate C-fiber phenotype based on the location of their cell bodies. One type of C-fiber is derived from neurons associated with the vagal nodose ganglion; the other C-fiber phenotype is associated more with the jugular vagal ganglia (and spinal dorsal root ganglia). Embryologically the nodose neurons are placodally derived, whereas the jugular and dorsal root ganglion neurons are derived from the neural crest. To understand the role of sensory C-fibers in health and disease, it is imperative that we develop a deeper understanding of these placodal and neural crest C-fiber phenotypes in the respiratory tract. This grant focuses attention on the idea that neural crest vs. placodal C-fiber phenotypes can be delineated not only on their activation profile, but also based on the location of their terminals within the lungs, and their neurotrophic regulation, and by the mechanisms regulating their excitability. In addition we begin to further develop the hypothesis that the reflex consequences of C-fiber activation will be strongly dependent on which C-fiber phenotype is activated. In the first aim we employ a very novel technique that we have developed that allows us to obtain detailed information regarding the relative location within the lungs of the terminals of the two C-fiber phenotypes. In the second aim we address specific hypotheses regarding relative neurotrophin regulation of the two C-fiber phenotypes in the respiratory tract. In the third aim we address the hypothesis that the excitability of the placodal C-fiber phenotype is enhanced due to express of a specific voltage-gated sodium channel (NaV1.9). In our last aim we address the hypothesis that activation of neural crest C-fiber phenotype enhances the cough reflex, whereas activation of placodal C-fibers actually inhibit the cough reflex. Each of the four aims of this grant is designed to provide novel information and insights into the neurobiology of C-fiber subtypes in the airways. We expect that this information will help build the framework from which future studies may be based that are aimed at understanding the role that these important nerves play in health and disease.

描述（由申请人提供）：气道中感觉 C 纤维神经的激活可导致咳嗽、打喷嚏、呼吸困难、反射性粘液分泌和气道狭窄。这些神经在保护气道免受潜在有害物质侵害方面发挥着重要作用，但在炎症性气道疾病中，它们的持续激活可能是许多与该疾病相关的症状和痛苦的根源。自从柯勒律治及其同事在 20 世纪 70 年代和 80 年代进行经典研究以来，人们至少在描述性水平上认识到，呼吸道中的迷走神经 C 纤维至少包含两种表型，通常称为“支气管 C 纤维”和“肺 C 纤维”。这种区别基于神经末梢的一般位置。我们建议根据细胞体的位置评估 C 纤维表型可能更有用。一种类型的 C 纤维源自与迷走神经节状神经节相关的神经元；另一种 C 纤维表型与颈静脉迷走神经节（和脊髓背根神经节）更多相关。从胚胎学角度来看，结节神经元源自盾板，而颈静脉神经节和背根神经节神经元则源自神经嵴。为了了解感觉 C 纤维在健康和疾病中的作用，我们必须更深入地了解呼吸道中的这些基板和神经嵴 C 纤维表型。这项资助的重点是这样一个想法：神经嵴与盾板 C 纤维表型不仅可以根据其激活曲线来描述，还可以根据其末端在肺内的位置、神经营养调节以及调节其兴奋性的机制来描述。此外，我们开始进一步发展这样的假设：C 纤维激活的反射后果将强烈依赖于哪种 C 纤维表型被激活。在第一个目标中，我们采用了我们开发的一种非常新颖的技术，该技术使我们能够获得有关两种 C 纤维表型末端在肺内相对位置的详细信息。在第二个目标中，我们提出了有关呼吸道中两种 C 纤维表型的相对神经营养素调节的具体假设。在第三个目标中，我们提出了这样的假设：由于特定电压门控钠通道 (NaV1.9) 的表达，盾板 C 纤维表型的兴奋性得到增强。在我们的最后一个目标中，我们提出了这样的假设：神经嵴 C 纤维表型的激活会增强咳嗽反射，而盾板 C 纤维的激活实际上会抑制咳嗽反射。该资助的四个目标均旨在提供有关气道 C 纤维亚型神经生物学的新颖信息和见解。我们期望这些信息将有助于构建未来研究的框架，旨在了解这些重要神经在健康和疾病中所发挥的作用。