Leukotriene B4 Receptors in Rheumatoid Arthritis

描述(申请人提供)：类风湿性关节炎(RA)是一种慢性自身免疫性炎症性疾病。中性粒细胞在类风湿滑膜中大量发现，并被认为与类风湿关节炎相关的炎症和疼痛的临床症状有关。中性粒细胞在宿主防御和炎症过程中的激活是由趋化物质的G蛋白偶联受体(GPCRs)介导的。白三烯B4(LTB4)是一种有效的中性粒细胞趋化因子，它激活其受体(BLT-1)，在中性粒细胞中介导多种生理效应。最近报道了第二个LTB4受体(BLT-2)，它具有独特的拮抗剂特异性和组织分布。GPCRs受受体磷酸化的调节，导致脱敏和下调。我们将验证这一假设，即LTB4通过高亲和力受体BLT-1介导其对RA中性粒细胞的影响，而LTB4通过BLT-2作用于RA调节T淋巴细胞的激活和功能。目前的研究目标是建立全面的体内和体外模型，以确定LTB4在小鼠RA发生发展中的作用以及BLT-1和BLT-2的相对贡献。在特定的目标1中，我们将确定BLT-1在胶原诱导性关节炎的发展和进展中的作用，我们已经通过靶向基因破坏产生了BLT-1缺陷小鼠。在具体目标2中，我们将使用成熟的RBL-2H3细胞模型来确定BLT-1和BLT-2在信号转导、脱敏、内化和拮抗剂专一性方面的差异。这些研究利用了我们最近开发的新的视频显微镜和活细胞成像方法。 白三烯参与了许多急、慢性炎症性疾病的病理生理过程，如全身过敏反应、动脉粥样硬化、类风湿关节炎和哮喘。了解不同的LTB4受体在缺乏特定受体的小鼠中的确切功能，并确定这些受体在RA中的作用，将为RA的治疗干预确定新的靶点。

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease. Neutrophils are found in large numbers in rheumatoid synovium and have been suggested to be involved in clinical signs of inflammation and pain associated with RA. Neutrophil activation during host defense and inflammation is mediated by G-protein coupled receptors (GPCRs) for chemoattractants. Leukotriene B4 (LTB4), a potent chemoattractant for neutrophils activates its receptor (BLT-1) to mediate diverse physiological effects in neutrophils. A second LTB4 receptor (BLT-2) with distinct antagonist specificity and tissue distribution was recently described. GPCRs are regulated by receptor phosphorylation leading to desensitization as well as down regulation. We will test the hypothesis that LTB4 acting through the high affinity receptor BLT-1 mediates its effects on neutrophils in RA, while LTB4 acting through BLT-2 modulates T-lymphocyte activation and function in RA. The goal of the current studies is to develop comprehensive in vivo and in vitro models to determine the role of LTB4 and the relative contributions of BLT-1 and BLT-2 in the development of murine RA. In specific aim 1 we will define the role of BLT-1 in the development and progression of collagen induced arthritis in the BLT-1 deficient mice we have already generated by targeted gene disruption. In specific aim 2 we will use the well-established RBL-2H3 cell model to determine the differences in signaling, desensitization, internalization and antagonist specificity of BLT-1 and BLT-2. These studies take advantage of the novel video microscopy and live cell imaging methods we have recently developed. Leukotrienes are involved in the pathophysiology of many acute and chronic inflammatory diseases such as systemic anaphylaxis, atherosclerosis, RA and asthma. Understanding the precise function of distinct LTB4 receptors in mice deficient in specific receptors and defining the role of these receptors in RA will identify novel targets for therapeutic intervention of RA.