Asthma, Airway Inflammation and Beta Chemokine Receptors

哮喘、气道炎症和 β 趋化因子受体

基本信息

批准号：
7921748
负责人：
CRAIG GERARD
金额：
$ 31.64万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-17 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7921748
关键词：
A549 Acute Affinity Allergens Allergic Allergic Reaction Antigens Asthma Attenuated CCR1 gene CX3C Chemokines CX3CL1 gene Cells Child Chronic Chronic Obstructive Airway Disease Data Dendritic cell activation Disease Family Fractalkine Functional disorder Funding GTP-Binding Proteins Genetic Genetic Polymorphism Glean Grant Host Defense Human Immune Immune response Individual Infection Inflammation Inflammatory Injury Ligation Lung Lung diseases Mediating Modeling Mus Natural Immunity Nature Organ Pathology Physiology Proteins Proteomics Reaction Role Site Tissues Validation Viral Virus Receptors Work airway hyperresponsiveness airway inflammation airway remodeling allergic airway inflammation beta-Chemokines cell type chemokine chemokine receptor drug development eosinophil glycoprotein G human GATA1 protein immune function immunopathology injured airway interest lung injury member mimetics pre-clinical promoter public health relevance receptor receptor function research study response response to injury

项目摘要

DESCRIPTION (provided by applicant): Great progress has been made over the past decade in elucidating pathophysiologic mechanisms in airways inflammatory diseases. Considerable controversy remains however, relating to the specific role of chemokines and their receptors in orchestrating the pathology. During the last funding cycle of this grant, we focused on two beta chemokine receptors, CCR1 and CCR3, examining their role, through the use of mice with genetic deletions, in several well-characterized models of lung disease. We additionally characterized eosinophil lineage ablated mice (?dblGATA) in both acute and chronic models of allergic airway inflammation. Our data support CCR3 ligation as the dominant mechanism for eosinophil recruitment, at baseline as well as in response to injury or infection. Using the ?dblGATA mice, we demonstrated that allergic airway hyperresponsiveness occurs in the absence of eosinophils, but that these cells may control features of airway remodeling. In Specific Aim 1 of this renewal application, we propose experiments to determine whether CCR3-/- mice are similarly protected from allergic airway remodeling. In preliminary studies we find a potential role for CCR1 in the pathophysiology of RSV infection, although complexities are revealed by superimposition of an allergic reaction. In our focus on airway hyperresponsiveness and the role of eosinophils, the newly gleaned variability in the role of this cell type appears to derive from subtleties in the mode of administration and nature of the allergen, as well as background mouse genetics. Since mice (and humans) develop airway hyperresponsiveness to RSV in the absence of an adaptive immune reaction, we have opted to investigate this mechanism of airway injury. We hypothesize a significant role for the fractalkine/CX3CR1 axis in RSV lung disease and will define the mechanism by which the RSV G glycoprotein subverts innate immune responses. Successful completion of these studies will provide additional mechanistic understanding of the pathophysiology of RSV induced lung injury as well as preclinical validation for drug development. PUBLIC HEALTH RELEVANCE: Since mice (and humans) develop airway hyperresponsiveness to RSV in the absence of an adaptive immune reaction, we have opted to investigate this mechanism of airway injury. We hypothesize a significant role for the fractalkine/CX3CR1 axis in RSV lung disease and will define the mechanism by which the RSV G glycoprotein subverts innate immune responses. Successful completion of these studies will provide additional mechanistic understanding of the pathophysiology of RSV induced lung injury as well as preclinical validation for drug development.

描述（由申请人提供）：过去十年在阐明气道炎症性疾病的病理生理机制方面取得了巨大进展。然而，关于趋化因子及其受体在病理学中的具体作用，仍然存在相当大的争议。在本次资助的最后一个资助周期中，我们重点研究了两种 β 趋化因子受体 CCR1 和 CCR3，通过使用具有基因缺失的小鼠，在几种特征明确的肺部疾病模型中检查了它们的作用。我们还在过敏性气道炎症的急性和慢性模型中对嗜酸性粒细胞谱系消融小鼠 (?dblGATA) 进行了表征。我们的数据支持 CCR3 连接作为基线以及响应损伤或感染时嗜酸性粒细胞募集的主要机制。使用 ?dblGATA 小鼠，我们证明过敏性气道高反应性在没有嗜酸性粒细胞的情况下发生，但这些细胞可能控制气道重塑的特征。在本次更新申请的具体目标 1 中，我们提出了实验来确定 CCR3-/- 小鼠是否同样能免受过敏性气道重塑的影响。在初步研究中，我们发现 CCR1 在 RSV 感染的病理生理学中具有潜在作用，尽管过敏反应的叠加揭示了复杂性。在我们对气道高反应性和嗜酸性粒细胞作用的关注中，新收集到的这种细胞类型作用的变异性似乎源自给药方式和过敏原性质的微妙之处，以及背景小鼠遗传学。由于小鼠（和人类）在缺乏适应性免疫反应的情况下会对 RSV 产生气道高反应性，因此我们选择研究这种气道损伤的机制。我们假设 fractalkine/CX3CR1 轴在 RSV 肺部疾病中发挥重要作用，并将定义 RSV G 糖蛋白颠覆先天免疫反应的机制。这些研究的成功完成将为 RSV 引起的肺损伤的病理生理学提供更多的机制理解，并为药物开发提供临床前验证。公共卫生相关性：由于小鼠（和人类）在缺乏适应性免疫反应的情况下会对 RSV 产生气道高反应性，因此我们选择研究这种气道损伤的机制。我们假设 fractalkine/CX3CR1 轴在 RSV 肺部疾病中发挥重要作用，并将定义 RSV G 糖蛋白颠覆先天免疫反应的机制。这些研究的成功完成将为 RSV 引起的肺损伤的病理生理学提供更多的机制理解，并为药物开发提供临床前验证。