Project 1 - Postnatal Development of Airway Trophic Interactions

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 过敏性哮喘在幼儿肺发育中的发展，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和间充质细胞（成纤维细胞，平滑肌）和基底 上皮/间充质营养单位内的膜区，具体目标如下： 1)明确出生后发育过程中臭氧和过敏原暴露对气道功能的影响 上皮细胞作为环境和其他组织之间的主要反应界面， 上皮/间质营养单位。 2)定义出生后发育期间臭氧和过敏原暴露对 基底细胞-基底膜带-成纤维细胞复合物作为细胞外基质的介质和来源 在上皮/间质营养单位内的腔上皮和基质之间的信号传导。 3)定义出生后发育过程中氧化剂和过敏原暴露对气道平滑的影响 肌肉作为基底细胞-基底膜带-成纤维细胞复合物信号传导的应答者， 作为产生和维持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.