MECHANISMS REGULATING AIRWAY EOSINOPHILIC INFLAMMATION

哮喘是一个主要的公共卫生问题。过敏原和病毒感染，如呼吸道合胞病毒(RSV)，是儿童哮喘的重要诱因。哮喘的病理特征是嗜酸性炎症。哮喘患者CC趋化因子的产生增加，是嗜酸性粒细胞的有力趋化因子。这项研究建议的中心假设是：为了应对RSV感染，呼吸道细胞产生趋化因子，吸引嗜酸性粒细胞进入呼吸道。嗜酸性粒细胞介质的释放会引起支气管痉挛和炎症，从而导致哮喘。为了全面了解调节气道嗜酸性炎症的机制，我们提出了四个基础研究项目。在项目1中，我们将描述嗜酸性粒细胞上的主要趋化因子受体CC趋化因子受体-3的信号转导机制。在项目2中，我们将研究RSV刺激的上皮细胞产生趋化因子的转录调控。在项目3中，我们将研究介导RSV激活嗜酸性粒细胞的受体和胞浆信号通路。在项目4中，我们将剖析CpG DNA基序抑制嗜酸性粒细胞炎症的机制。项目4中，我们将利用病毒学、细胞生物学、免疫学、信号转导和基因转录控制方面的跨学科专家之间的现有和资助的合作者。这一独特的研究人员组合将以最全面和多学科的方式在细胞和分子水平上解决呼吸道炎症的发病机制。该提案寻求应用协同方法来解决哮喘问题。该中心的具体方面将开发和测试针对哮喘过敏性炎症的新型治疗药物，并可能作为有效的RSV疫苗的辅助药物。

Asthma is a major public health problem. Allergens and viral infections, e.g. respiratory syncytial virus (RSV), are important precipitants of childhood asthma. The pathologic hallmark of asthma is an eosinophilic inflammation. The production of CC chemokines is increased in asthma and they are potent chemoattractants of eosinophils. The central hypothesis of this research proposal is that: In response to RSV infection, the airway cells produce chemokines that attract eosinophils into the airways. The release of eosinophil mediators causes bronchospasm and inflammation leading to asthma. In order to provide a comprehensive understanding of mechanisms regulating airway eosinophilic inflammation, we present four basic research projects. We will delineate the signal transduction mechanism of the CC chemokine receptor-3, the principal chemokine receptor on eosinophils in project 1. We will study the transcriptional regulation of chemokine production by RSV- stimulated epithelial cells in project 2. We will study receptors and cytosolic signaling pathways that mediate RSV activation of eosinophils in project 3. Further, we will dissect the mechanism by which CpG DNA motifs inhibit eosinophilic inflammation in project 4. The proposal utilizes existing and funded collaborators between cross-disciplinary project leaders expert in virology, cell biology, immunology, signal transduction, and control of gene transcription. This unique combination of investigators will address the pathogenesis of airway inflammation at a cellular and molecular level in a most comprehensive and multi- disciplinary manner. The proposal seeks to apply synergistic approaches to solving problems in asthma. Specific aspects of this center will develop and test novel therapeutic agents that target allergic inflammation of asthma and may be adjunct to an effective RSV vaccine.