The Neural Mechanism of Respiratory Allergies and Infections

摘要 过敏性鼻炎是最常见的粘膜过敏。它的主要症状包括过度打喷嚏。 和鼻漏，严重影响我们的生活质量和生产力。尽管抗组胺药物有效 缓解间歇性轻度变应性鼻炎引起的打喷嚏，但对持续性无效 中度/重度过敏性鼻炎。缓解过敏性打喷嚏的新药开发受到阻碍 缺乏关于调节打喷嚏的主要鼻感觉神经元及其与鼻部的相互作用的信息 免疫细胞。在这项提议中，我们假设高度受限的鼻感觉神经元群体 由mrgprC11的表达定义检测变应性鼻炎中的肥大细胞介质并触发打喷嚏 条件反射。在目标1中，我们将描述鼻黏膜中表达mrgprc11的纤维的神经支配模式。 并用基因标记和轴突示踪技术检测变应性鼻炎时的病理变化 接近了。此外，我们将测定它们对各种引起打喷嚏的生理反应。 分子使用一种新的体外钙成像工具。这些研究将提供有关 鼻腔刺激物的初步检测和打喷嚏信号的传递。在目标2中，我们将定义 急性打喷嚏时的mrgprC11纤维。我们将确定MRgprC11神经元的消融是否会减弱 打喷嚏对各种鼻部刺激物的反应以及是否选择性激活MRgprC11感觉纤维 在鼻黏膜中会引起打喷嚏。这些研究将确定mrgprC11感觉纤维是否 用于不同感官刺激引起的打喷嚏。在目标3中，我们将研究神经免疫 变应性鼻炎中鼻感觉纤维与肥大细胞的相互作用。我们将测试一下 脱颗粒的肥大细胞激活mrgprC11鼻感觉纤维，在变应性鼻炎中诱导打喷嚏。 此外，我们将确定药物抑制mrgprc11感觉纤维是否可行。 控制与变应性鼻炎相关的打喷嚏的治疗策略。这些研究不仅将推动我们的 对引发打喷嚏的神经免疫相互作用的了解，也提供了一个新的神经元靶点 用于控制鼻部过敏症状。

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.