Eosinophil-mediated Sensory Neuroplasticity in Asthma

哮喘中嗜酸性粒细胞介导的感觉神经可塑性

基本信息

批准号：
9341949
负责人：
Katherine Michelle Lebold
金额：
$ 4.9万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9341949
关键词：
Acetylcholine Afferent Neurons Agonist Allergens Animals Asthma Biopsy Blood Vessels Breathing Bronchoconstriction Capsaicin Cations Chest Chronic Coculture Techniques Complex Coughing Dimensions Epithelial Exhibits Extravasation Functional disorder Goals Growth Growth Factor Histologic House Dust Mite Allergens Human In Vitro Inflammation Laboratories Laser Scanning Confocal Microscopy Lead Length Leukocytes Life Limb structure Lung Maps Measurement Measures Mediating Methods Modeling Morphology Mus Nerve Nerve Fibers Neuronal Plasticity Neurons Neuropeptides Neurotransmitter Receptor Neurotransmitters Optics Patients Pharmacology Physiological Pulmonary Inflammation Reflex action Resistance Role Sensory Shortness of Breath Skin Spinal Ganglia Stimulus Structure Substance P Symptoms TRPV1 gene Thick Thinness Tissue imaging Tissues Transgenic Mice Transgenic Model Wild Type Mouse afferent nerve airway hyperresponsiveness airway inflammation allergic airway inflammation asthmatic airway asthmatic patient density digital eosinophil human disease imaging modality in vivo mRNA Expression mouse model nerve supply novel protein expression public health relevance receptor receptor expression reconstruction response therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Sensory nerves narrow airways in response to inhaled substances. Patients with asthma exhibit enhanced sensitivity and reactivity to inhaled stimuli, leading to life-threatening bronchoconstriction and symptoms such as shortness of breath and chest tightness. The mechanisms of airway nerve hyperreactivity are unclear and represent a potential therapeutic target. Eosinophils accumulate within the airways of asthmatic patients and interact with nerves. Eosinophils also increase cultured sensory nerve growth. The goal of this project is to determine if eosinophils cause airway hyperreactivity by regulating sensory nerve morphology, as well as neurotransmitter and receptor expression. This project proposes to use whole-mount immunostaining, tissue optical clearing, laser-scanning confocal microscopy, and digitized nerve modeling to characterize how eosinophils regulate nerve morphology and neurotransmitter content in murine models of asthma. Measurements of lung resistance in mice treated with selective pharmacologic antagonists will determine how eosinophil-mediated sensory neuroplasticity promotes airway hyperreactivity. This project also proposes to co- culture primary human sensory neurons with eosinophils to determine if eosinophils increase expression of select neurotransmitters and receptors. Taken together, achieving the goals of this proposal will increase understanding of how eosinophils promote airway nerve dysfunction in asthmatic patients.

描述（适用提供）：感官神经响应遗传物质而狭窄的气道。哮喘暴露的患者对遗传刺激的敏感性和反应性增强，导致威胁生命的支气管收缩和症状，例如呼吸和胸部紧绷。气道神经过度反应性的机制尚不清楚，代表了潜在的治疗靶点。嗜酸性粒细胞积聚在哮喘患者的气道中，并与神经相互作用。嗜酸性粒细胞还增加了培养的感觉神经生长。该项目的目的是确定嗜酸性粒细胞是否通过调节感觉神经形态以及神经递质和受体表达来引起气道高反应性。该项目建议使用全置免疫染色，组织光学清除，激光扫描共聚焦显微镜以及数字化神经建模，以表征嗜酸性粒细胞如何调节哮喘鼠模型中的嗜酸性神经形态和神经递质含量。用选择性药理学拮抗剂治疗的小鼠中肺阻力的测量将决定嗜酸性粒细胞介导的感觉神经可塑性如何促进气道高反应性。该项目还建议与嗜酸性粒细胞共同培养原代人感觉神经元，以确定嗜酸性粒细胞是否增加了精选神经递质和受体的表达。综上所述，实现该提案的目标将增加对嗜酸性粒细胞如何促进哮喘患者气道神经功能障碍的理解。