Project 1 - Postnatal Development of Airway Trophic Interactions

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 儿童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。 该项目将侧重于上皮细胞和间充质细胞(成纤维细胞、平滑肌细胞)和基底 上皮/间充质营养单位内的膜带，具体目的如下： 1)确定出生后发育过程中臭氧和过敏原暴露对呼吸道功能的影响 上皮作为环境和其他部分之间的主要反应界面 上皮/间充质营养单位。 2)确定出生后发育过程中臭氧和过敏原暴露对 基底细胞-基膜带-成纤维细胞复合体既是细胞外的介质又是细胞外的来源 腔上皮和上皮/间充质营养单位内基质之间的信号传递。 3)明确出生后发育过程中接触氧化剂和过敏原对呼吸道顺畅的影响 肌肉作为基底细胞-基底膜带-成纤维细胞复合体信号的响应者 作为产生和维护细胞外信号环境的参与者。

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/mesenchymal 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 the epithelial and mesenchymal cells (fibroblasts, smooth muscle) and the basement membrane zone within the epithelial/mesenchymal trophic unit, with the following specific aims: 1) Define the impact ozone and allergen exposure during postnatal development on the function of airway epithelium as the principle reactive interface between the environment and the rest of the epithelial/mesenchymal trophic unit. 2) Define the impact of ozone and allergen exposure during postnatal development on the function of the basal cell-basement membrane zone-fibroblast complex as both a mediator and a source of extracellular signaling between luminal epithelium and the matrix within the epithelial/mesenchymal trophic unit. 3) Define the impact of oxidant and allergen exposure during postnatal development on the airway smooth muscle as a responder to signaling from the basal cell-basement membrane zone-fibroblast complex and as a player in generating and maintaining the extracellular signaling milieu.