Role of the Leukotriene B4 Receptors in Asthma

描述(申请人提供)：哮喘现在被认为是一种 呼吸道炎症性疾病。嗜酸性粒细胞、中性粒细胞、巨噬细胞和 淋巴细胞也被招募到呼吸道中。花生四烯酸 白三烯B4衍生物及其受体是血管紧张素转换酶的重要介导物。 白细胞趋化性。LTB4信号转导通路参与了卵巢癌的发病机制。 哮喘和这种疾病的小鼠模型。然而，准确的角色是 LTB4受体BLTR1和BLTR2在哮喘病理生物学中的作用还不完全 为人所知。我们的实验室最近产生了一种靶向的小鼠品系 BLTR1(BLTR1-/-)编码基因缺失。初步实验 在哮喘的小鼠模型中使用这种小鼠品系显示出减少了 嗜酸性粒细胞被招募到呼吸道。我们的假设是LTB4是一种 在这一哮喘模型中对白细胞的重要趋化剂及其 作用主要通过BLTR1受体介导。我们还建议 LTB4信号在气道重塑的发生发展中起重要作用。 具体地，我们试图确定以下内容：1)BLTR1信令是否 嗜酸性粒细胞、中性粒细胞和巨噬细胞的募集 2)BLTR1是否影响T细胞的募集和分布 该模型中呼吸道和淋巴结中的淋巴细胞；3)BLTR1信号 在呼吸道高反应性和粘液产生中起重要作用；4)如果BLTR1 信号对慢性哮喘模型中的气道重塑的影响；5)如果新的 所描述的受体BLTR2在这个小鼠模型中有任何功能作用 哮喘。利用BLTR1-/-小鼠的哮喘模型，我们希望准确地定义 BLTR1在哮喘发病机制中的作用在存在的情况下重复实验 BLTR2拮抗剂也将允许表征这一过程的作用 哮喘中的受体。

DESCRIPTION (provided by the applicant): Asthma is now recognized as an inflammatory disease of the airways. Eosinophils, neutrophils, macrophages and lymphocytes, are also recruited into the airways. The arachidonic acid derivative leukotriene B4 (LTB4) and its receptors are important mediators of leukocyte chemotaxis. LTB4 signaling has been implicated in the pathogenesis of asthma and in a murine model of this disorder. However, the precise role of the LTB4 receptors, BLTR1 and BLTR2, in the pathobiology of asthma is incompletely known. Our laboratory has recently generated a mouse strain with a targeted deletion in the gene that codes for BLTR1 (BLTR1-/-). Preliminary experiments using this mouse strain in a murine model of asthma have shown a reduction in eosinophils recruited into the airways. Our hypothesis is that LTB4 is an important chemoattractant for leukocytes in this model of asthma and that its actions are mediated primarily through the BLTR1 receptor. We also propose that LTB4 signaling is important in the development of airway remodeling. Specifically we seek to determine the following: 1) if BLTR1 signaling is important for the recruitment of eosinophils, neutrophils, and macrophages in this model of asthma; 2) if BLTR1 effects the recruitment and profile of T lymphocytes in the airways and lymph nodes in this model; 3) if BLTR1 signaling is important in airways hyperreactivity and mucous production; 4) if BLTR1 signaling effects airway remodeling in a chronic asthma model; 5) if the newly described receptor BLTR2 has any functional role in this murine model of asthma. Using a model of asthma in BLTR1-/- mice we hope to precisely define the role of BLTR1 in asthma pathogenesis. Repeat experiments in the presence of a BLTR2 antagonist will also allow characterization of the role of this receptor in asthma.