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.

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。 这一更新应用的重点将放在环境引起的青少年哮喘的机制上。 儿童，使用我们建立的恒河猴环境过敏性哮喘模型 通过对这个项目的支持。在过去五年的资助中，使用这种模式，我们已经做出了 关于长期接触臭氧对肺发育和肺发育的影响的惊人发现 婴儿期生长，包括：呼吸道发育迟缓，出生后呼吸道代数减少，受损 基底细胞建立成纤维细胞生长因子-2三元信号复合体，上皮细胞表面失败 中枢神经控制受损，过敏反应增强，呼吸道高反应性， 肺泡化和呼吸道重塑被破坏。所有研究提出的分析框架 对于这种更新将进行的是上皮/间充质营养单位，其细胞成分 通过基底膜调节的细胞外信号复合体建立营养相互作用 区域。 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。 该项目将重点研究上皮/间充质营养单位内的粘膜免疫，具体如下 具体目标： 1)确定间歇性臭氧暴露与对室内尘螨(HDM)的致敏作用 过敏原可在出生后发育过程中启动哮喘表型。 2)确定间歇性臭氧暴露与对HDM过敏原的致敏作用如何 与哮喘表型的进展有关。 3)确定间歇性臭氧暴露与对HDM过敏原的致敏作用如何导致 哮喘表型持续到成年早期。