The Neural Mechanism of Respiratory Allergies and Infections

摘要 过敏性鼻炎是最常见的粘膜过敏。其主要症状包括打喷嚏过多 和腹泻，严重影响我们的生活质量和生产力。虽然抗组胺药有效地 缓解间歇性轻度过敏性鼻炎引起的打喷嚏，对持续性过敏性鼻炎无效。 中度/重度过敏性鼻炎。缓解过敏性喷嚏的新药的开发受到以下因素的阻碍： 缺乏关于调节打喷嚏的主要鼻感觉神经元及其与 免疫细胞在这个提议中，我们假设一个高度有限的鼻感觉神经元群体， 通过MrgprC 11的表达来定义检测肥大细胞介质在变应性鼻炎中的作用并触发打喷嚏 反射。在目的1中，我们将描述鼻粘膜中MrgprC 11表达纤维的神经支配模式 应用基因标记和轴突追踪技术检测变应性鼻炎时的病理变化 接近。此外，我们还将确定他们对各种诱发喷嚏的生理反应。 分子使用一种新的离体钙成像工具。这些研究将提供重要信息， 鼻刺激物的初始检测和打喷嚏信号的转导。在目标2中，我们将定义 急性打喷嚏中的MrgprC 11+纤维我们将确定MrgprC 11+神经元的消融是否减弱了 对各种鼻刺激物的打喷嚏反应以及MrgprC 11+感觉纤维是否选择性激活 会引起打喷嚏这些研究将确定MrgprC 11+感觉纤维是否 所需的不同感官刺激诱发打喷嚏。在目标3中，我们将研究神经免疫 变应性鼻炎中MrgprC 11+鼻感觉纤维和肥大细胞之间的相互作用我们将测试 脱颗粒肥大细胞激活MrgprC 11+鼻感觉纤维以诱导变应性鼻炎中的打喷嚏。 此外，我们将确定是否药理学沉默MrgprC 11+感觉纤维是一个可行的， 控制与过敏性鼻炎相关的打喷嚏的治疗策略。这些研究不仅将促进我们的 了解引发打喷嚏的神经免疫相互作用，但也提供了一个新的神经靶点 控制鼻过敏症状

Abstract Allergic rhinitis is the most common mucosal allergy. Its cardinal symptoms include excessive sneezing and rhinorrhea, which severely impact our life quality and productivity. Although antihistamines effectively relieved sneezing induced by intermittent mild allergic rhinitis, they are ineffective against persistent moderate/severe allergic rhinitis. The development of new drugs for alleviating allergic sneezing is hindered by a lack of information about the principal nasal sensory neurons that mediate sneezing and their interactions with immune cells. In this proposal, we hypothesize that a highly restricted population of nasal sensory neurons defined by the expression of MrgprC11 detect mast cell mediators in allergic rhinitis and trigger the sneezing reflex. In Aim 1, we will characterize the innervation pattern of MrgprC11-expressing fibers in the nasal mucosa and examine their pathological changes under allergic rhinitis using genetic labeling and axonal tracing approaches. Furthermore, we will determine their physiological responses to a variety of sneeze-inducing molecules using a novel ex vivo calcium-imaging tool. These studies will provide important information on the initial detection of nasal irritants and transduction of sneezing signals. In Aim 2, we will define the role of MrgprC11+ fibers in acute sneezing. We will determine whether ablation of MrgprC11+ neurons attenuates sneezing responses to a variety of nasal irritants and whether selective activation of MrgprC11+ sensory fibers in the nasal mucosa evokes sneezing. These studies will establish whether MrgprC11+ sensory fibers are required for sneezing induced by different sensory stimuli. In Aim 3, we will investigate the neuro-immune interactions between MrgprC11+ nasal sensory fibers and mast cells in allergic rhinitis. We will test whether degranulated mast cells activate MrgprC11+ nasal sensory fibers to induce sneezing in allergic rhinitis. Furthermore, we will determine whether pharmacological silencing of MrgprC11+ sensory fibers is a feasible therapeutic strategy to control sneezing associated with allergic rhinitis. These studies will not only advance our understanding of the neuro-immune interactions that trigger sneezing, but also provide a novel neuronal target for controlling nasal allergic symptoms.