Neuroimmune interactions for laryngeal sensorimotor neuropathy in postviral influenza infection

病毒性流感感染后喉部感觉运动神经病变的神经免疫相互作用

• 批准号: 10827254
• 负责人: Alexander G Foote
• 金额: $ 6.91万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-21 至 2026-08-20
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10827254
• 关键词: ASCL1 gene; Acute; Address; Affect; Animals; Attention; Cell physiology; Cells; Chronic; Clinical Treatment; Coughing; Data; Diagnostic; Disease; Dysplasia; Efferent Neurons; Environment; Epithelium; Etiology; Faculty; Functional disorder; Genetic; Goals; Health; Hypersensitivity; Image; Immune; Immune response; Infection; Inflammation; Inflammatory; Influenza A virus; Injury; Knockout Mice; Laryngeal Epithelium; Laryngeal Mucosa; Laryngismus; Larynx; Link; Lung; Maps; Mediating; Mentors; Modeling; Motor; Mucositis; Mucous Membrane; Nerve; Neuroendocrine Cell; Neuroimmune; Neuroimmunomodulation; Neurons; Neuropathy; Neurosecretory Systems; Organ; Outcome; Paralysed; Pathway interactions; Peptides; Physiology; Population; Postdoctoral Fellow; Research; Research Personnel; Resolution; Respiratory Signs and Symptoms; Role; Science; Secretory Cell; Sensorimotor functions; Sensory; Signal Transduction; Specialist; Testing; Therapeutic; Tissues; Transgenic Animals; Upper Respiratory Infections; Upper respiratory tract; Vagus nerve structure; Viral; Virus; Virus Diseases; Voice; Work; afferent nerve; airway hyperresponsiveness; arm; cell type; conditional knockout; effective therapy; efficacy testing; experimental study; improved; influenza infection; innovation; insight; mouse genetics; mouse model; mutant; neural; neural circuit; neuroinflammation; neuroregulation; neurosensory; neurotransmitter release; novel; programs; repaired; sensor; sensory neuropathy; therapeutic target; transcriptome; transcriptomics; vocal cord

ABSTRACT The larynx is richly innervated with nerves, forming neuroimmune niches that constitute the basis for bidirectional interactions in mucosal defense and physiology. Idiopathic sensorimotor abnormalities of the larynx, such as acute vocal fold paralysis and chronic hypersensitivity (chronic cough, episodic laryngospasm) are attributed to upper respiratory tract infections with a viral etiology. However, a causal link for viral-induced laryngeal pathophysiology remains tenuous. In this application, I will employ an established model of influenza A virus (IAV) infection to interrogate laryngeal mucosal remodeling and map afferent/efferent neural circuits/cells in naïve and virus infected tissues. I will investigate the central hypothesis that viral infection of the larynx will activate neurosensory cells, remodel both afferent and efferent nerves, contributing to mucosal inflammation and hypersensitivity. I will test this hypothesis utilizing a combination of mouse genetics, whole tissue clearing and imaging, single-cell transcriptomics and live animal functional testing. We anticipate that these activated neural inflammatory signals are detected via a unique population of ASCL1+ neuroendocrine and CHAT+ cells that drive a neurosensory-immune circuit for laryngeal neuropathy. Together, these experiments are expected to ascertain neural sensorimotor circuits and reveal neuroimmune interactions for coordinating repair pathways following viral-induced mucosal inflammation. We expect findings will guide the field in new directions for innovating treatments for laryngeal and vocal fold inflammatory diseases and sensorimotor neuropathies.

抽象的 喉部富含神经支配，形成构成构成基础的神经免疫壁ni 粘膜防御和生理学中的双向相互作用。特发性感觉运动异常 喉，例如急性声折叠瘫痪和慢性超敏反应（慢性咳嗽，情节性喉痉挛） 归因于具有病毒病因的上呼吸道感染。但是，病毒诱导的因果关系 喉病理生理学仍然很少。在此应用程序中，我将采用既定的影响力模型 一种病毒（IAV）感染，以询问喉粘膜重塑并映射传入/传出神经元 幼稚和病毒感染组织中的圆圈/细胞。我将调查中心假设，即 喉将激活神经感觉细胞，重塑传入和有效的神经，有助于粘膜 炎症和超敏反应。我将利用小鼠遗传学的组合来检验这一假设 组织清除和成像，单细胞转录组学和活动物功能测试。我们预料到这一点 这些激活的神经炎症信号通过ASCL1+神经内分泌的独特种群检测到 和CHAT+细胞，驱动喉神经病的神经感觉免疫电路。在一起，这些 实验有望确定神经感觉运动电路，并揭示了神经免疫性相互作用 病毒引起的粘膜注射后协调修复途径。我们希望发现将指导 针对喉和声带炎症性疾病的创新治疗的新方向领域 感觉运动神经病。