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

项目摘要 吸入空气中携带的有害化合物和外来物质不断攻击鼻腔，可能会导致 严重的鼻炎。在世界范围内，数以亿计的成年人和儿童患有哮喘， 鼻-鼻窦炎和其他呼吸道疾病。环境刺激物和细菌感染会引发这些 鼻炎的类型。在鼻道中，炎症触发物的检测主要是通过中介实现的 通过三叉神经化学感觉系统和孤立的化学感觉细胞(SCCs)。已知的配体 SCCS是一种苦味化合物苯甲酸变性，用于几种家用产品，以及酰基 细菌感染产生的高丝氨酸内酯(AHL)。SCCS，它表达了苦的元素 味觉(T2R)转导通路由三叉神经纤维支配，三叉神经纤维传递它们对 中枢神经系统，触发神经肽释放到粘膜，引发炎症/免疫 反应和呼吸保护反射，以消除刺激性化合物。变性和AHL是 在干细胞中激活T2R途径的典型化合物。因此，研究它们对干细胞的影响 可以增加我们对呼吸道化学感受和暴露于鳞状细胞癌的长期影响的了解 触发点。在这项拟议的研究中，我们将确定变性和细菌对SCC的激活 AHLS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 变性菌可引发与细菌感染相同的鼻部炎症和免疫反应(目标2)； 强迫暴露于变性或AHL是否会损害嗅觉上皮，以及SCCs是否 在这些情况下提供保护(目标3)。因为社交、工作和其他情况通常需要人们 忽略SCC触发的生理警告，并呆在刺激性和有毒的环境中 化合物的存在，重要的是要了解SCCs的功能和确定化学感受性 常见刺激性化合物的作用机制和生理/行为效应 变性。了解这些反应中涉及的转导级联反应和机制将提供 针对几种呼吸道疾病的新的选择性药理靶点。

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.