Interleukin-13 in Experimental Asthma

描述(由申请人提供)： 在过去的50年里，发达国家因哮喘导致的残疾和死亡人数有所增加。一种细胞因子，IL-13，已经被动物和人类研究强烈地与哮喘的发病机制有关。因此，IL-13已成为开发哮喘新疗法的重要靶点。更好地了解IL-13的产生、调节和效应机制是优化任何与IL-13相关的治疗所必需的。本计划项目通过综合研究IL-13在哮喘小鼠模型中的重要性来回应这一要求。项目I将使用基因靶向小鼠来评估IL-13抑制肺上皮细胞表达的Na+/K+/2CI-共转运体NKCC1与IL-13诱导的呼吸道高反应性(AHR)和粘液过度产生之间的联系。项目2将评估IL-13的独特特性，使其在哮喘中比类似的细胞因子IL-4更重要。这一部分的实验将以在单细胞类型或除单细胞类型之外的所有细胞上表达IL-13受体的IL-4Rpha成分的小鼠为特色，以及对似乎仅由IL-13诱导的一小部分基因的研究。项目3将评估IL-13、趋化因子和嗜酸性粒细胞之间的相互作用如何协同作用促进肺部炎症，并将评估一种趋化因子Mig如何抑制IL-13的影响。项目4将评估IL-13结合蛋白IL-13R-Alpha2如何对IL-13诱导的AHR和呼吸道炎症具有积极和消极的影响。所有科学组成部分将通过产生和共享动物和试剂，并通过建立一个概念框架，以便对所有获得的数据进行最佳解释，从而相互作用。行政、“病理学和基因表达”和“育种和基因分型”核心将促进研究人员之间的合作，并提高拟议研究的执行效率。综合所进行的研究，应能全面了解IL-13在实验性哮喘中的独特作用。

DESCRIPTION (provided by applicant): Disability and death caused by asthma has increased in developed nations during the past 50 years. One cytokine, IL-13, has been strongly implicated in asthma pathogenesis by both animal and human studies. Consequently, IL-13 has become an important target for developing novel asthma therapies. Better understanding of the production, regulation, and effector mechanisms of IL- 13 is required to optimize any IL-13 related therapy. This Program Project responds to this requirement by investigating the importance of IL-13 in mouse models of asthma in an integrated fashion. Project I will use gene-targeted mice to evaluate the connection between IL-13 suppression of NKCC1, a Na+/K+/2CI- co-transporter expressed by lung epithelial cells, and IL-13 induction of airway hyperresponsiveness (AHR) and mucus overproduction. Project 2 will evaluate the unique characteristics of IL-13 that make it more important than the similar cytokine, IL-4, in asthma. Experiments in this component will feature mice that express the IL-4Ralpha component of the IL- 13 receptor on a single cell type or on all cells but a single cell type, as well as studies of a small set of genes that appear to be induced exclusively by IL-13. Project 3 will evaluate how interactions among IL-13, chemokines, and eosinophils act synergistically to promote pulmonary inflammation and will evaluate how one chemokine, Mig, can inhibit the effects of IL-13. Project 4 will evaluate how an IL-13-binding protein, IL-13R-alpha2, has both positive and negative effects on IL-13-induced AHR and airway inflammation. All scientific components will interact with each other by generating and sharing animals and reagents and by creating a conceptual framework that allows for optimal interpretation of all acquired data. Administrative, "Pathology and Gene Expression," and "Breeding and Genotyping" cores will promote collaborations between the investigators and improve the efficiency with which the proposed studies are performed. Integration of the studies performed should provide a comprehensive understanding of the unique role of IL-13 in experimental asthma.