Project 1 - Postnatal Development of Airway Trophic Interactions

项目 1 - 气道营养相互作用的产后发育

• 批准号: 8069606
• 负责人: CHARLES George PLOPPER
• 金额: $ 43.59万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8069606
• 关键词: Acute; Air Pollutants; Allergens; Allergic; Asthma; Basal Cell; Basement membrane; Breathing; Cells; Characteristics; Child; Childhood; Chronic; Complex; Development; Differentiation and Growth; Environment; Environmental Exposure; Epithelial; Epithelium; Equilibrium; Exposure to; Extrinsic asthma; Failure; Fibroblast Growth Factor 2; Fibroblasts; Funding; Generations; Goals; Growth; Growth and Development function; Homeostasis; Immune; Immune response; Infant; Inflammation; Inflammatory; Injury; Lung; Macaca mulatta; Mediator of activation protein; Mesenchymal; Modeling; Myofibroblast; Nerve; Oxidants; Ozone; Pattern; Phenotype; Predisposition; Proteins; Pyroglyphidae; Recording of previous events; Respiratory System; Rest; Role; Severities; Signal Transduction; Signaling Molecule; Smooth Muscle; Source; Sulfhydryl Compounds; Surface; Time; airway epithelium; airway hyperresponsiveness; airway remodeling; allergic airway disease; allergic response; cholesterol epoxide; critical period; early childhood; environmental stressor; extracellular; infancy; lung development; oxidation; oxidized lipid; ozone exposure; postnatal; programs; repaired; 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/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.

该计划的整体目标是因为其成立是为了定义 哺乳动物呼吸系统吸入环境浓度的氧化剂空气污染物。重点 这种更新的应用将是关于幼儿环境引起的哮喘的机制， 我们通过支持开发的婴儿恒河猴环境过敏的模型 这个程序。在过去五年的资金中使用此模型，我们令人震惊 关于慢性臭氧对婴儿期肺发育和生长的影响的发现， 包括：气道增长的阻碍，产后流动后代丧失，FGF-2的建立受损 基底细胞的三元信号传导复合物，上皮表面的失败因支配而受损中枢神经 控制，增强过敏反应，气道高反应性，肺泡化干扰和气道 重塑。为此续签提出的所有研究的分析框架是 上皮/间质营养单元，其细胞成分通过A建立营养相互作用 细胞外信号传导复合物由基底膜区域调制。 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 在幼儿发育中的肺部发育过敏性哮喘，并通过以下方式加剧其严重程度：（1） 破坏上皮/间质营养单元中的稳态，（2）根本上妥协 促进正常气道增长和的营养相互作用的建立和差异 发展。这些变化是由于急性损伤，炎症连续循环的叠加而导致的， 并修复对过敏原暴露的免疫反应。 该项目将重点放在上皮细胞和间质细胞（成纤维细胞，平滑肌）和地下室 上皮/间质营养单元内的膜区，具有以下特定目的： 1）定义产后发育过程中对气道功能的冲击臭氧和过敏原暴露 上皮作为环境和其余部分之间的反应性接口 上皮/间质营养单元。 2）定义产后发育过程中臭氧和过敏原暴露对功能的影响 基底细胞膜膜区纤维细胞复合物作为介体和细胞外源 上皮/间质营养单元内的腔上皮和基质之间的信号传导。 3）定义产后发育过程中氧化剂和过敏原暴露在气道方面的影响 肌肉是从基底细胞膜膜区域成纤维细胞复合物中发出信号的响应者 作为生成和维护细胞外信号环境的玩家。