Role of Eotaxin-3/CCL26 in Allergic Asthma

Eotaxin-3/CCL26 在过敏性哮喘中的作用

基本信息

批准号：
7201730
负责人：
Lisa A Miller
金额：
$ 7.55万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-02-01 至 2009-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7201730
关键词：
Address Allergens Animal Model Area Asthma Attenuated Basement membrane Biology Characteristics Childhood Asthma Clinical Trials Complex Deposition Development Disease Effector Cell Environment Eosinophilia Eotaxin Extracellular Matrix Proteins Extrinsic asthma Future Granulocyte-Macrophage Colony-Stimulating Factor Homologous Gene Human Hypersensitivity Infant Infiltration Interferon Type II Interleukin-10 Interleukin-3 Interleukin-4 Interleukin-5 Interleukin-6 Investigation Laboratories Leukotrienes Lung Mediating Mediator of activation protein Medicine Modeling Molecular Monkeys Monoclonal Antibodies Mucous Membrane Mus Mutant Strains Mice Neurotoxins Ovalbumin Pathogenesis Pathologic Phenotype Play Positioning Attribute Primates Prostaglandins Proteins Reporting Resources Role Small inducible cytokine A24 Source T-Lymphocyte Therapeutic Transforming Growth Factor alpha Transforming Growth Factor beta airborne allergen airway epithelium airway hyperresponsiveness airway remodeling allergic airway disease attenuation base chemokine comparative cytokine eosinophil experience human CCL26 protein mouse model nonhuman primate novel prevent programs trafficking

项目摘要

DESCRIPTION (provided by applicant): T lymphocytes that express a Th2 cytokine profile play a pivotal role in the development of allergic airways disease, yet it is clear from numerous studies that eosinophils also contribute to the pathogenesis of asthma. Our laboratory has recently investigated eotaxin/CCL11, eotaxin-2/CCL24, and eotaxin-3/CCL26 as chemokine mediators of allergen-induced eosinophil recruitment using a non-human primate model 'of childhood asthma. We have demonstrated that allergen-induced eosinophil recruitment into the infant monkey lung significantly correlates with elevated expression of eotaxin-3/CCL26 within airway epithelium. Based on these findings, we hypothesize that eotaxin-3/CCL26 expression by airway epithelium plays an important role in the trafficking of eosinophils into airways following aeroallergen exposure. To address our hypothesis, the primary objective of this R03 pilot proposal is to develop a mouse model to assess the functional role of eotaxin-3/CCL26 in the development of allergic airways disease. The first specific aim of this application will focus on cellular and molecular approaches to characterize a mouse homologue for human eotaxin-3/CCL26. The second specific aim will subsequently generate an eotaxin-3/CCL26 targeted deletion mutant mouse which, following sensitization with ovalbumin, will define the pathologic role for this eosinophilic chemokine within the context of an allergic asthma model. At the completion of this project, we will have defined a putative pathophysiologic role for a novel eosinophilic chemokine; this will contribute to our overall understanding of how the complex chemokine network within the lung regulates trafficking of eosinophils in allergic asthma. The identification of chemokines that promote allergic asthma is an important step in the future development of therapeutics to target specific molecules within the airways.

描述（由申请人提供）：表达Th2细胞因子特征的T淋巴细胞在过敏性气道疾病的发展中起关键作用，但是从大量研究中可以明显看出，嗜酸性粒细胞也有助于哮喘的发病机理。我们的实验室最近研究了使用非人类灵长类动物模型'儿童哮喘的eotaxin/ccl11，eotaxin-2/ccl24和eotaxin-3/ccl26作为过敏原诱导的嗜酸性嗜酸性粒细胞募集的趋化因子介质。我们已经证明，过敏原诱导的嗜酸性粒细胞募集到婴儿猴肺中，与气道上皮中eotaxin-3/ccl26的表达升高显着相关。基于这些发现，我们假设气道上皮的eotaxin-3/ccl26表达在空气过敏原暴露后将嗜酸性粒细胞贩运到气道中起重要作用。为了解决我们的假设，该R03试点建议的主要目标是开发小鼠模型，以评估eotaxin-3/ccl26在过敏性气道疾病发展中的功能作用。该应用的第一个具体目的将集中在细胞和分子方法上，以表征人Eotaxin-3/CCL26的小鼠同源物。第二个特定目的将随后产生eotaxin-3/ccl26靶向缺失突变小鼠，在用卵巢蛋白敏化后，它将在过敏性哮喘模型的背景下定义该嗜酸性粒细胞趋化因子的病理作用。该项目完成时，我们将定义一种新型嗜酸性趋化因子的假定病理生理作用。这将有助于我们对肺部复杂趋化因子网络如何调节嗜酸性粒细胞在过敏性哮喘中的运输。促进过敏性哮喘的趋化因子的鉴定是靶向靶向气道内特定分子的未来发展的重要一步。