Project 2 - Postnatal Development of Pulmonary Immune Mechanisms

项目2——产后肺部免疫机制的发育

• 批准号: 7089293
• 负责人: Reen Wu
• 金额: $ 21.52万
• 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/7089293
• 关键词: Macaca mulatta; active immunization; age difference; air pollution; airborne allergen; asthma; cell cell interaction; early experience; immunomodulators; juvenile animal; longitudinal animal study; lung development; mature animal; mesenchyme; mucosal immunity; newborn animals; oxidizing agents; ozone; pathologic process; pyroglyphid; respiratory epithelium; smooth muscle

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 mucosal immunity within the epithelial/mesenchymal trophic unit, with the following specific aims: 1) Determine how episodic ozone exposure in conjunction with sensitization to house dust mite (HDM) allergen can initiate the asthma phenotype during postnatal development. 2) Determine how episodic ozone exposure in conjunction with sensitization to HDM allergen can contribute to the progression of the asthma phenotype. 3) Determine how episodic ozone exposure in conjunction with sensitization to HDM allergen can result in persistence of the asthma phenotype into early adulthood.

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。 该更新应用的重点将放在年轻的环境诱发哮喘的机制上 儿童，使用我们已经开发的婴儿恒河猴中环境过敏性哮喘的模型 通过支持该程序。在过去五年的资金中使用此模型，我们做了一个 关于慢性臭氧暴露对肺部发育的影响的惊人发现数量 婴儿期的生长，包括：气道增长的阻滞，产后流气道的损失受损 通过基底细胞建立FGF-2三元信号传导复合物，上皮表面失败 支配，中枢神经控制受损，过敏反应增强，气道高反应性， 肺泡化和气道重塑。所有研究提出的分析框架 因为这种续订将进行上皮/间质营养单元，其细胞成分 通过基底膜调制的细胞外信号传导复合物建立营养相互作用 区。 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。 该项目将集中于上皮/间质营养单元内的粘膜免疫 具体目的： 1）确定情节性臭氧如何与敏化对房屋尘螨（HDM）结合使用 过敏原可以在产后发育过程中启动哮喘表型。 2）确定情节性臭氧暴露与对HDM过敏原的敏感性如何有助于 哮喘表型的进展。 3）确定情节性臭氧暴露与对HDM过敏原的敏感性如何导致 哮喘表型的持久成年早期。