Airway Sensory Neuroexcitability

描述(申请人提供)：呼吸道中C-纤维感觉神经的激活可导致咳嗽、打喷嚏、呼吸困难、反射性粘液分泌和呼吸道狭窄。这些神经在保护呼吸道免受潜在破坏性物质的伤害方面发挥了重要作用，但在炎症性呼吸道疾病中，它们的持续激活可能是许多症状和与这种疾病相关的大部分痛苦的基础。自从Coleridges和他们的同事在20世纪70年代和80年代进行经典研究以来，人们已经认识到，至少在描述性水平上，呼吸道中的迷走神经C纤维至少包括两种表型，通常被称为“支气管C纤维”和“肺C纤维”。根据神经末梢的大致位置进行区分。我们认为，根据细胞体的位置来评估C纤维的表型可能更有用。一种C纤维来源于与迷走神经节相关的神经元；另一种C纤维表型更多地与颈静脉迷走神经节(和脊背根神经节)相关。在胚胎学上，结状神经元来自胎盘，而颈静脉和背根神经节神经元则来自神经脊。为了了解感觉C纤维在健康和疾病中的作用，我们必须对呼吸道中的这些胎盘和神经脊C纤维表型有更深入的了解。这项资助侧重于这样一个观点，即神经脊和胎盘C纤维的表型不仅可以根据它们的激活情况来描述，还可以基于它们在肺内的终末位置、它们的神经营养调节以及它们的兴奋性调节机制来描述。此外，我们开始进一步发展这样的假设，即C纤维激活的反射结果将强烈依赖于C纤维被激活的表型。在第一个目的中，我们使用了一种我们开发的非常新的技术，该技术允许我们获得关于两个C纤维表型的终末在肺内的相对位置的详细信息。在第二个目标中，我们提出了关于呼吸道中两种C纤维表型的相对神经营养素调节的具体假设。在第三个目的中，我们提出的假设是胎盘C纤维表型的兴奋性由于特定的电压门控钠通道(NaV1.9)的表达而增强。在我们的最后一个目标中，我们解决了这样的假设，即激活神经脊C纤维表型增强了咳嗽反射，而激活胎盘C纤维实际上抑制了咳嗽反射。这项资助的四个目标中的每一个都旨在为呼吸道中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，未来的研究可能以此为基础，旨在了解这些重要神经在健康和疾病中所起的作用。 与公共卫生相关：呼吸道中感觉C纤维神经的激活可导致咳嗽、打喷嚏、气喘感、反射性粘液分泌和呼吸道狭窄。这些神经在保护呼吸道免受潜在破坏性物质的伤害方面发挥了重要作用，但在炎症性呼吸道疾病中，它们的持续激活可能是与这种疾病相关的许多症状和痛苦的基础。这笔赠款旨在增加我们对呼吸道中感觉C纤维性质的了解，以便能够实现旨在限制与炎症性呼吸道疾病相关的痛苦的策略。

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. PUBLIC HEALTH RELEVANCE: 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 with the disorder. This grant is designed to increase our understanding of the nature of sensory C-fibers in the airways so that strategies aimed at limiting the suffering associated with inflammatory airway diseases can be realized.