Sensory C Fibers in the Upper Airways

描述（由申请人提供）： 过敏性炎症、手术干预、空气污染物和烟草烟雾引起的上呼吸道感觉神经的激活引发心肺和上呼吸道反射。反射和感觉包括打喷嚏、瘙痒、充血、粘液分泌、支气管痉挛、呼吸模式改变、动脉低血压和心动过缓。给定反射反应的特定性质可能是由于被激活的上气道传入神经的类型。然而，这一领域的进展受到了限制，缺乏有关上呼吸道感觉神经亚型及其激活机制的信息。在目的1中，我们将解决新的假设，即有两个不同的化学敏感性（伤害感受器C-纤维）感觉神经亚型支配上呼吸道的激活配置文件的基础上，神经递质含量和他们支配的粘膜面积。在目标2和3中，我们将研究上气道介导反射的关键刺激物对这些亚型的激活。具体而言，在目标2中，我们将解决与瞬时受体电位A1（TRPA 1）在上呼吸道伤害感受器激活中的作用有关的假设。TRPA 1受体被广泛的外源性物质激活，包括污染物，食品和烟草烟雾成分。TRPA 1受体也是G蛋白偶联受体活化后下游信号传导事件的靶标（例如缓激肽B2受体）。此外，我们提出了新的假设，TRPA 1受体直接激活内源性产生的前列腺素15-脱氧delta 12，14-前列腺素J2，PGD 2的代谢产物。在目标3中，我们将提出特定肥大细胞介质通过两种不同机制影响上呼吸道伤害感受器活性的假设：“激活”和“改变兴奋性”。我们还将评估这些事件发生的机制。我们将使用解剖学和电生理学技术的组合来解决我们的假设。总体而言，目标1中的研究将在指导阶段（K99）进行，目标2和3将在本提案的独立阶段（R 00）进行。

DESCRIPTION (provided by applicant): Activation of sensory nerves in the upper airways by allergic inflammation, surgical intervention, airborne pollutants and tobacco smoke initiates cardiopulmonary and upper airway reflexes. Reflexes and sensations include sneezing, itch, congestion, mucus secretion, bronchospasm, altered respiratory pattern, arterial hypotension and bradycardia. The specific nature of a given reflex response is likely due to the type of upper airway afferent nerve that is activated. However, progress in this area has been limited by a lack of information regarding upper airways sensory nerve subtypes and their mechanisms of activation. In Aim 1, we will address the novel hypothesis that there are two distinct chemosensitive (nociceptor C-fiber) sensory nerve subtypes innervating the upper airways based on activation profile, neurotransmitter content and the area of the mucosa they innervate. In Aims 2 and 3 we will study the activation of these subtypes by key stimulants of upper airways-mediated reflexes. Specifically, in Aim 2, we will address hypotheses relating to the role of transient receptor potential A1 (TRPA1) in the activation of upper airways nociceptors. TRPA1 receptors are activated by a wide range of exogenous substances including pollutants, foodstuffs and tobacco smoke constituents. TRPA1 receptors are also targets for downstream signaling events following G-protein coupled receptor activation (e.g. bradykinin B2 receptors). In addition we present the novel hypothesis that TRPA1 receptors are directly activated by the endogenously-produced prostanoid 15-deoxydelta12,14- prostaglandin J2, a metabolite of PGD2. In Aim 3 we will address the hypotheses that specific mast cell mediators effect upper airway nociceptor activity via 2 distinct mechanisms: "activation" and "altered excitability". We will also evaluate the mechanisms by which these events occur. We will use a combination of anatomical and electrophysiological techniques to address our hypotheses. Overall, studies in Aim 1 will be carried out during the mentored phase (K99), with Aims 2 and 3 being performed in the independent phase (R00) of this proposal.