ASTHMA, AIRWAY INFLAMMATION AND BETA CHEMOKINE RECEPTORS

描述(改编自申请人的摘要)：贩运 淋巴细胞和嗜酸性粒细胞进入肺是哮喘和 其他肺部疾病。这些细胞定位和定位的机制 在呼吸道中被激活的情况还不是很清楚。趋化因子是一种 阳离子肝素结合型趋化因子基因家族的多样性 多肽。它们被合成并从上皮细胞中释放出来， 内皮细胞和造血细胞对不同刺激的反应。 细胞因子、生长因子、病毒颗粒和其他自体激素放大 通过趋化因子的炎症反应。多个趋化因子与一种 白细胞上G蛋白偶联受体的有限谱系。这个 研究人员假设β趋化因子受体在炎症反应中 细胞对构成和活跃的嗜酸性粒细胞募集是必不可少的 致敏状态下的淋巴细胞向肺内转移。这 假设将通过三个具体目标进行检验。1)识别、克隆 并鉴定小鼠的β-趋化因子受体。三种β趋化因子 受体将被克隆、表达和生化鉴定为 配基结合和信号传递特性。这些基因在体内的表达 受体将在RNA和蛋白质水平上进行分析。2)删除测试版 通过基因打靶从小鼠基因组中提取趋化因子受体。基因 将在单个ES系中通过同源基因来制备基因敲除 重组，导致单一β趋化因子缺乏的动物 受体。为了控制潜在的受体冗余， “双淘汰赛”将在一条线上进行，以产生具有 CCR1和CCR3缺乏症。3)表型鉴定 趋化因子受体缺失在呼吸道模型中的后果 发炎。主要的炎症模型将使用雾化吸入 致敏小鼠的白蛋白。这些目标的成功实现将 阐明β-趋化因子作用的体内必需信息 在呼吸道炎症中。因此，β趋化因子受体(S)是 潜在的关键靶点在理解发病机制和 哮喘和其他炎症性肺部疾病的潜在治疗。

DESCRIPTION (Adapted from the applicant's abstract): The trafficking of lymphocytes and eosinophils to the lung is characteristic of asthma and other lung diseases. The mechanisms by which these cells are localized and activated in the airways are not well understood. The chemokines are a diverse gene family of cationic, heparin binding chemoattractant polypeptides. They are synthesized and released from epithelium, endothelium and hematopoietic cells in response to diverse stimuli. Cytokines, growth factors, virus particles and other autocoids amplify the inflammatory response via chemokines. Multiple chemokines interact with a limited repertoire of G-protein coupled receptors on leukocytes. The investigators hypothesize that the beta chemokine receptors on inflammatory cells are essential to constitutive as well as active eosinophil recruitment to the lung, and lymphocytes trafficking in the sensitized state. This hypothesis will be tested with three specific aims. 1) To identify, clone and characterize murine beta chemokine receptors. Three beta chemokine receptors will be cloned, expressed and biochemically characterized for ligand binding and signalling properties. The in vivo expression of these receptors will be analyzed at the RNA and protein levels. 2) To delete beta chemokine receptors from the mouse genome through gene targeting. Gene knockouts will be prepared in individual ES lines by homologous recombination, giving rise to animals deficient in a single beta chemokine receptor. In order to control for potential receptor redundancy, "double-knockouts" will be targeted in a single line, to yield animals with deficiency of both CCR1 and CCR3. 3) To evaluate the phenotypic consequences of chemokine receptor deletion in models of airways inflammation. The primary inflammatory model will utilize aerosolized albumin in sensitized mice. The successful completion of these aims will yield essential in vivo information clarifying the role of beta chemokines in airways inflammation. Thus, the beta chemokine receptor(s) are potentially a critical target in understanding the pathogenesis and potential management of asthma and other inflammatory lung diseases.