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: 7089295
• 负责人: EDWARD S SCHELEGLE
• 金额: $ 19.28万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7089295
• 关键词: Macaca mulatta; age difference; air pollution; airborne allergen; asthma; early experience; immune response; immunomodulators; innervation; longitudinal animal study; lung development; lymphocyte; mature animal; mesenchyme; muscle contraction; neuroregulation; newborn animals; ozone; parasympathetic nervous system; pathologic process; phenotype; pyroglyphid; respiratory epithelium; sensory signal detection; smooth muscle; sympathetic nervous system

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.

这一计划的总体目标是从一开始就确定猪的病理生物学反应 哺乳动物呼吸系统要吸入周围浓度的氧化剂空气污染物。焦点 这项更新申请的内容将是关于环境引起的幼儿哮喘的机制，使用 我们通过支持建立的恒河猴环境过敏性哮喘幼年模型 这个节目的一部分。在过去五年的融资中，使用这种模式，我们取得了一些令人震惊的成就 关于婴儿时期长期接触臭氧对肺部发育和生长的影响的发现， 包括：呼吸道生长发育迟缓，出生后呼吸道代数减少，成纤维细胞生长因子-2的建立受损 由基底细胞组成的三元信号复合体，上皮表面未能神经支配，受损的中枢神经 控制、过敏反应增强、呼吸道高反应性、肺泡化紊乱和呼吸道 改建。建议进行这次更新的所有研究的分析框架是 上皮/间充质营养单位，其细胞成分通过 由基底膜带调控的细胞外信号复合体。 这项计划的总体假设是，环境中暴露于氧化性空气污染物会促进 幼儿发育期肺部过敏性哮喘的发生，并通过以下方式加重其严重性：1) 破坏上皮/间充质营养单位内的动态平衡和2)从根本上损害 促进正常呼吸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、 并修复对过敏原暴露的免疫反应。 该项目将专注于上皮/间充质营养单位内的神经支配和神经控制， 以下是具体目标： 1)确定吸入臭氧和/或屋尘螨(HDM)变应原对 上皮/间充质营养中的传导通道及其与生长因子和信号的关系 在出生后发育的关键窗口，以及这些变化是否持续到成年生活。 2)确定间歇性吸入臭氧和/或HDM变应原对感觉神经活动的影响 在出生后发育和发育的关键窗口期间的多个呼吸道世代和结构 确定这些变化是否会持续到成年生活。 3)确定接触臭氧和/或HDM变应原导致 由于神经控制的改变而导致的平滑肌收缩能力的持续变化。 4)确定交感神经和交感神经之间平衡的早期和持续变化 副交感神经对呼吸道相关淋巴结的活动调节抗原识别和 淋巴细胞的表型，并决定这种调节是否会持续到成年。