Airway Sensory Neuroexcitability

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、呼吸急促感、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损害物质的影响方面发挥着重要作用，但在炎症性气道疾病中，它们的不断激活可能是许多症状和许多与疾病相关的痛苦的基础。自20世纪70年代和80年代Coleridges及其同事的经典研究以来，至少在描述性水平上已经认识到，呼吸道中的迷走C纤维包括至少两种表型，通常称为“支气管C纤维”和“肺C纤维”。区别基于神经末梢的一般位置。我们建议，它可能是更有用的C-纤维表型的基础上，其细胞体的位置进行评估。一种类型的C-纤维来源于与迷走神经结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）相关。在胚胎学上，结状神经元来源于基板，而颈静脉和背根神经节神经元来源于神经嵴。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。这项资助关注的想法是，神经嵴与基板C-纤维表型不仅可以根据其激活特征来描绘，而且还可以根据其终端在肺内的位置，以及其神经营养调节，以及调节其兴奋性的机制。此外，我们开始进一步发展假设，即C纤维激活的反射结果将强烈依赖于哪种C纤维表型被激活。在第一个目标中，我们采用了一种非常新颖的技术，我们已经开发，使我们能够获得详细的信息，在肺内的两个C-纤维表型的终端的相对位置。在第二个目标，我们解决具体的假设相对神经营养调节的两个C-纤维表型在呼吸道。在第三个目标，我们解决的假设，基板C-纤维表型的兴奋性增强，由于表达的特定电压门控钠通道（NaV1.9）。在我们的最后一个目标，我们解决的假设，激活神经嵴C-纤维表型增强咳嗽反射，而基板C-纤维的激活实际上抑制咳嗽反射。这项资助的四个目标中的每一个都旨在为气道中C纤维亚型的神经生物学提供新的信息和见解。我们希望这些信息将有助于建立一个框架，未来的研究可能会基于这个框架，旨在了解这些重要神经在健康和疾病中的作用。

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.