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激活了上呼吸道的感觉神经，启动了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。特定反射反应的特定性质可能是由于激活的上呼吸道传入神经的类型所致。然而，由于缺乏关于上呼吸道感觉神经亚型及其激活机制的信息，这一领域的进展一直受到限制。在目标1中，我们将提出一个新的假设，即根据激活曲线、神经递质含量和它们所支配的粘膜面积，存在两种不同的化学敏感性(伤害性感受器C纤维)感觉神经亚型。在目标2和目标3中，我们将研究上呼吸道介导的反射的关键刺激物对这些亚型的激活。具体地说，在目标2中，我们将解决与瞬时受体电位A1(TRPA1)在激活上呼吸道伤害性感受器中的作用有关的假设。TRPA1受体被广泛的外源物质激活，包括污染物、食品和烟草烟雾成分。TRPA1受体也是G蛋白偶联受体激活后下游信号事件的靶点(例如，缓激素B2受体)。此外，我们提出了一个新的假设，即TRPA1受体是由内源性产生的前列腺素15-脱氧-12，14-前列腺素J2直接激活的，前列腺素J2是PGD2的代谢物。在目标3中，我们将提出以下假设：特定的肥大细胞介质通过两种不同的机制影响上呼吸道伤害性感受器的活动：“激活”和“兴奋性改变”。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的研究将在指导阶段(K99)进行，目标2和目标3将在本提案的独立阶段(R00)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.