Project 3 - Postnantal Development of Airway Neural Control

项目 3 - 产后气道神经控制的发展

• 批准号: 7422372
• 负责人: EDWARD S SCHELEGLE
• 金额: $ 19.98万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7422372
• 关键词: Acute; Address; Adult; Air Pollutants; Allergens; Allergic; Animals; Antigens; Asthma; Basal Cell; Basement membrane; Breathing; Characteristics; Child; Chronic; Complex; Cues; Development; Differentiation and Growth; Disruption; Efferent Neurons; Environmental Exposure; Epithelial; Equilibrium; Exposure to; Extrinsic asthma; Failure; Fibroblast Growth Factor 2; Funding; Generations; Goals; Growth; Growth Factor; Growth and Development function; Homeostasis; House Dust; House Dust Mite Allergens; Immune response; Infant; Inflammation; Injury; Life; Lower respiratory tract structure; Lung; Lung Compliance; Lymphocyte; Macaca mulatta; Mesenchymal; Modeling; Monkeys; Nerve; Nerve Tissue; Neuraxis; Neurons; Numbers; Oxidants; Ozone; Phenotype; Predisposition; Pyroglyphidae; Recording of previous events; Respiratory System; Sensory; Severities; Signal Transduction; Smooth Muscle; Structure; Surface; afferent nerve; airway hyperresponsiveness; airway remodeling; animal tissue; density; extracellular; infancy; lung development; lymph nodes; nerve supply; neuronal guidance; neuroregulation; ozone exposure; postnatal; programs; pulmonary function; pyroglyphid; relating to nervous system; repaired; research study; respiratory smooth muscle; response

The overall goal of this program since its inception has been to define the pathobiological response of the mammalian respiratory system to the inhalation of ambient concentrations of oxidant air pollutants. The focus of this renewal application will be on mechanisms of environmentally induced asthma in young children, using the model of environmental allergic asthma in infant rhesus monkeys that we have developed through support of this program. Using this model over the previous five years of funding, we have made a number of startling discoveries regarding the effect of chronic ozone exposure on lung development and growth during infancy, including: stunting of airway growth, postnatal loss of airway generations, impaired establishment of the FGF-2 ternary signaling complex by basal cells, the failure of epithelial surfaces to innervate, impaired central nervous control, enhancement of the allergic response, airway hyperreactivity, disrupted alveolarization, and airway remodeling. The analytical framework in which all of the studies proposed for this renewal will be conducted is the epithelial/mesenchymal trophic unit, whose cellular components establish trophic interactions via an extracellular signaling complex modulated by the basement membrane zone. The overall hypothesis for this program is that environmental exposure to oxidant air pollutants promotes the development of allergic asthma in the developing lungs of young children and exacerbates its severity by: 1) disrupting the homeostasis within the epithelial/mesenchymai trophic unit and 2) fundamentally compromising the establishment and differentiation of the trophic interactions that promote normal airway growth and development. These changes result from the superimposition of continual cycles of acute injury, inflammation, and repair on the immune response to allergen exposure. This Project will focus on innervation and neural control within the epithelial/mesenchymal trophic unit, with the following specific aims: 1) Determine the impact of O3 and/or house dust mite (HDM) allergen inhalation on the sensory innervation of the conducting airways, its relation to growth factors and cues within the epithelial/mesenchymal trophic unit during critical windows of postnatal development, and whether these changes persist into adult life. 2) Determine the impact of episodic O3 and/or HDM allergen inhalation on the sensory nerve activity arising from multiple airway generations and structures during critical windows of postnatal development and determine whether these changes persist into adult life. 3) Determine the critical window of susceptibility when exposure to O3 and/or HDM allergen results in persistent changes in smooth muscle contractility due to altered neural control. 4) Determine how the early and continued alteration in the balance between sympathetic and parasympathetic nerve activity to airway-associated lymph nodes modulates antigen recognition and lymphocyte phenotype and determine whether this modulation persist into adult life.

该计划自启动以来的总体目标是确定疾病的病理生物学反应 哺乳动物的呼吸系统吸入环境浓度的氧化剂空气污染物。焦点 该更新应用程序的重点是环境诱发幼儿哮喘的机制，使用 我们通过支持开发的幼年恒河猴环境过敏性哮喘模型 这个程序的。在过去五年的资助中，我们利用这种模式取得了许多令人震惊的成果 关于长期接触臭氧对婴儿期肺部发育和生长影响的发现， 包括：气道生长迟缓、产后气道世代丧失、FGF-2 建立受损 基底细胞的三元信号复合体、上皮表面神经支配失败、中枢神经受损 控制、增强过敏反应、气道高反应性、破坏肺泡化和气道 重塑。进行本次更新提议的所有研究的分析框架是 上皮/间质营养单位，其细胞成分通过 由基底膜区调节的细胞外信号复合物。 该计划的总体假设是，环境暴露于氧化剂空气污染物会促进 幼儿肺部发育中出现过敏性哮喘，并通过以下方式加剧其严重程度：1) 破坏上皮/间质营养单位内的稳态，2) 从根本上损害 促进正常气道生长的营养相互作用的建立和分化 发展。这些变化是急性损伤、炎症、 以及修复对过敏原暴露的免疫反应。 该项目将重点关注上皮/间质营养单位内的神经支配和神经控制， 以下具体目标： 1) 确定吸入 O3 和/或屋尘螨 (HDM) 过敏原对感觉神经支配的影响 传导气道，其与生长因子的关系以及上皮/间质营养中的线索 出生后发育关键时期的单位，以及这些变化是否持续到成年生活。 2) 确定间歇性 O3 和/或 HDM 过敏原吸入对感觉神经活动的影响 来自产后发育关键时期的多个气道世代和结构 确定这些变化是否持续到成年生活中。 3) 确定暴露于 O3 和/或 HDM 过敏原导致的敏感性临界窗口 由于神经控制改变导致平滑肌收缩力持续变化。 4）确定交感神经和交感神经之间的平衡如何早期和持续改变。 气道相关淋巴结的副交感神经活动调节抗原识别和 淋巴细胞表型并确定这种调节是否持续到成年生活。