ASTHMA, AIRWAY INFLAMMATION AND BETA CHEMOKINE RECEPTORS

描述（改编自申请人的摘要）： 淋巴细胞和嗜酸性粒细胞的肺是哮喘的特征， 其他肺部疾病。 这些细胞定位的机制， 在气道中激活的是不太清楚的。 趋化因子是一种 阳离子肝素结合化学引诱物的多样性基因家族 多肽。 它们由上皮细胞合成和释放， 内皮细胞和造血细胞对各种刺激的反应。 细胞因子、生长因子、病毒颗粒和其他类原质放大了 炎症反应通过趋化因子。 多种趋化因子与 白细胞上G蛋白偶联受体的有限库。 的 研究者假设炎症细胞上的β趋化因子受体 细胞对于嗜酸性粒细胞的组成性募集和活性募集是必不可少的 到达肺部，并在致敏状态下运输淋巴细胞。 这 我们将以三个具体目标来检验这一假设。 1)鉴定，克隆 并表征鼠β趋化因子受体。 三β趋化因子 受体将被克隆、表达和生物化学表征， 配体结合和信号传导性质。 这些基因的体内表达 受体将在RNA和蛋白质水平上进行分析。 2)删除测试版 通过基因靶向从小鼠基因组中提取趋化因子受体。 基因 敲除将在单个ES系中通过同源的 重组，导致动物缺乏单一β趋化因子 受体的 为了控制潜在的受体冗余， “双重敲除”将在单一品系中靶向，以产生具有以下特征的动物： CCR1和CCR3都缺乏。 3)为了评估表型 气道模型中趋化因子受体缺失的后果 炎症 原发性炎症模型将使用雾化吸入的 致敏小鼠中的白蛋白。 这些目标的成功实现将 产生阐明β趋化因子作用的重要体内信息 呼吸道炎症 因此，β趋化因子受体是 可能是理解发病机制的关键目标， 哮喘和其他炎性肺病的潜在管理。

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.