The Neural Mechanism of Respiratory Allergies and Infections

呼吸道过敏和感染的神经机制

• 批准号: 10612424
• 负责人: Qin Liu
• 金额: $ 51.71万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-14 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10612424
• 关键词: Ablation; Acute; Address; Afferent Neurons; Air; Allergens; Allergic; Allergic rhinitis; Antihistamines; Attenuated; Axon; Basic Science; Behavior; Behavioral; Brain Stem; Burning Pain; Calcium; Capsaicin; Cell Degranulation; Cells; Chemicals; Chili Pepper; Chronic; Clinical; Clinical Research; Common Core; Defense Mechanisms; Detection; Development; Environmental Irritants; Esthesia; Fiber; G-Protein-Coupled Receptors; Genetic; Histamine; Human; Hypersensitivity; IgE; Imaging Device; Immune; Immunologics; Infection; Irritants; Label; Light; Lung; Mediating; Mediator; Modeling; Mucous Membrane; Mus; Neuroimmune; Neurons; Nose; Pathologic; Pattern; Physiological; Pilot Projects; Play; Population; Productivity; Property; Pruritus; Quality of life; Reflex action; Respiration; Role; Sensory; Signal Transduction; Sneezing; Stimulus; Structure of mucous membrane of nose; Structure of trigeminal ganglion; Symptoms; Testing; Therapeutic; Wild Type Mouse; aerosolized; cholinergic; designer receptors exclusively activated by designer drugs; fiber cell; genetic approach; imaging approach; insight; mast cell; nerve supply; neuromechanism; neuropeptide FF; neurotransmission; new therapeutic target; novel; novel therapeutics; pathogen; pharmacologic; prevent; response; sensory stimulus; symptomatology

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.

抽象的 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Rhinorrhea，这严重影响了我们的生活质量和生产力。尽管有效地抗组胺药 间歇性轻度过敏性鼻炎引起的释放的打喷嚏，对持续性无效 中度/严重的过敏性鼻炎。减轻过敏性打喷嚏的新药的开发受到了阻碍 缺乏有关介导打喷嚏及其与其相互作用的主要鼻感官神经元的信息 免疫细胞。在此提案中，我们假设鼻感觉神经元受到严格限制 由MRGPRC11的表达定义 反射。在AIM 1中，我们将表征鼻粘膜表达MRGPRC11的神经模式 并使用遗传标记和轴突追踪检查其在过敏性鼻炎下的病理变化 方法。此外，我们将确定他们对各种打喷嚏的生理反应 使用新型的离体钙成像工具的分子。这些研究将提供有关 初始检测鼻刺激物和打喷嚏信号的转导。在AIM 2中，我们将定义 MRGPRC11+急性打喷嚏的纤维。我们将确定消融MRGPRC11+神经元是否减弱 对各种鼻刺激物的打喷嚏反应以及MRGPRC11+感觉纤维的选择性激活是否是否 在鼻粘膜中，唤起打喷嚏。这些研究将确定MRGPRC11+感觉纤维是否是 由不同的感觉刺激引起的打喷嚏所必需的。在AIM 3中，我们将研究神经免疫 MRGPRC11+鼻感觉纤维与肥大细胞之间的相互作用。我们将测试是否 脱粒的肥大细胞激活MRGPRC11+鼻感觉纤维，以诱导过敏性鼻炎打喷嚏。 此外，我们将确定MRGPRC11+感觉纤维的药理沉默是否是可行的 控制与过敏性鼻炎相关的打喷嚏的治疗策略。这些研究不仅会推动我们的 了解引发打喷嚏的神经免疫相互作用，但也提供了一种新型的神经元靶标 用于控制鼻过敏症状。