Project 3 - Postnantal Development of Airway Neural Control

该计划自成立以来的总体目标是确定患者的病理生物学反应， 哺乳动物的呼吸系统吸入环境浓度的氧化剂空气污染物。重点 这次更新申请的一部分将是关于幼儿环境诱发哮喘的机制， 环境过敏性哮喘的婴儿恒河猴模型，我们已经通过支持开发， 这个项目的。在过去五年的资助中，我们使用这种模式， 关于长期臭氧暴露对婴儿期肺发育和生长的影响的发现， 包括：呼吸道生长发育迟缓，出生后呼吸道发育丧失，FGF-2的建立受损， 基底细胞的三元信号复合物，上皮表面神经支配的失败，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 重塑为这次更新提出的所有研究将采用的分析框架是： 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 过敏性哮喘在幼儿发育中的肺中的发展，并通过以下方式加剧其严重程度：1） 破坏上皮/间充质营养单位内的稳态，和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、 并修复对过敏原暴露的免疫反应。 本项目将重点研究上皮/间充质营养单位内的神经支配和神经控制， 具体目标如下： 1)确定O3和/或屋尘螨（HDM）过敏原吸入对感觉神经支配的影响， 传导气道，其与上皮/间充质营养细胞内生长因子和线索的关系 在出生后发育的关键窗口期间，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 在出生后发育的关键窗口期间， 确定这些变化是否持续到成年生活。 3)当暴露于O3和/或HDM过敏原导致以下结果时，确定敏感性的临界窗口 由于神经控制的改变而导致平滑肌收缩力的持续变化。 4)确定早期和持续的交感神经和 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。

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.