Role of solitary chemosensory cells in irritant avoidance and protection of olfactory sensation

项目摘要 吸入的空气中携带的有害化合物和异生物质不断攻击鼻腔， 严重的鼻腔炎症。在世界范围内，数以亿计的成人和儿童患有哮喘， 鼻窦炎和其他呼吸系统疾病。环境刺激物和细菌感染可以引发这些 鼻炎症的类型。在鼻道中，炎症触发物的检测主要是介导的 通过三叉神经化学感受系统和孤束化学感受细胞（SCC）。的已知配体 SCC是一种苦味化合物苯甲酸地那铵，用于多种家用产品， 高丝氨酸内酯（AHLs）由细菌感染产生。SCC表达了苦味的成分， 味觉（T2 R）转导级联，由三叉神经纤维支配，三叉神经纤维将它们的反应传递给味觉（T2 R）转导级联。 中枢神经系统，触发神经肽释放到粘膜中，引起炎症/免疫 消除刺激性化合物的反应和自我保护反射。地那铵和AHLs是 用于活化SCC中T2 R途径的原型化合物。因此，研究它们对SCC的影响 可以增加我们对气道化学感受和暴露于SCC的长期影响的理解 触发器在这项拟议的研究中，我们将确定是否SCC激活变性和细菌 AHL触发回避行为，防止进一步吸入这些刺激物（目标1）;是否存在 与细菌感染相同的地那铵引发鼻腔炎症和免疫反应（目的2）;以及 强迫暴露于地那铵或AHLs是否会损伤嗅上皮， 在这种情况下的保护（目标3）。因为社会、工作和其他情况往往要求人们 忽视SCC引发的生理警告，并留在刺激性和毒性的环境中， 化合物存在时，重要的是要了解SCC如何发挥作用，并确定化学感受性 机制和生理/行为的影响，常见的刺激性化合物，如 地那铵了解这些反应中涉及的转导级联和机制将提供 几种气道病变的新的选择性药理学靶点。

Project Summary Harmful compounds and xenobiotics carried in inhaled air continually assault the nasal cavity and can cause severe nasal inflammation. Worldwide, hundreds of millions of adults and children suffer with asthma, rhinosinusitis, and other respiratory conditions. Environmental irritants and bacterial infections can trigger these types of nasal inflammation. In the nasal passages, the detection of inflammation triggers is mostly mediated by the trigeminal chemosensory system and the solitary chemosensory cells (SCCs). Known ligands of the SCCs are the bitter compound denatonium benzoate, used in several household products, and acyl homoserine lactones (AHLs) generated by bacterial infections. SCCs, which express elements of the bitter taste (T2R) transduction cascade, are innervated by trigeminal nerve fibers, which relay their responses to the central nervous system, triggering release of neuropeptides into the mucosa, evoking inflammatory/immune responses and respiratory-protective reflexes to eliminate the irritating compounds. Denatonium and AHLs are prototypical compounds for the activation of the T2R pathway in SCCs. Thus, studying their effects on SCCs can increase our understanding of airway chemoreception and of long-term effects of exposure to SCC triggers. In this proposed research, we will determine whether SCC activation by denatonium and bacterial AHLs triggers avoidance behavior, preventing further inhalation of these irritants (Aim 1); whether the presence of denatonium triggers the same nasal inflammation and immune response as bacterial infections (Aim 2); and whether forced exposure to denatonium or AHLs can damage the olfactory epithelium and if SCCs are protective in these circumstances (Aim 3). Because social, work, and other situations often require people to ignore physiological warnings triggered by SCCs and stay in environments where irritating and toxic compounds are present, it is important to understand how SCCs function and to determine the chemosensory mechanisms and the physiological/behavioral effects of commonly encountered irritant compounds like denatonium. Understanding the transduction cascades and mechanisms involved in these responses will offer new selective pharmacological targets for several airway pathologies.