Leukotriene B4 Receptors in Rheumatoid Arthritis

描述（由申请人提供）：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性滑膜中大量存在，并被认为与RA相关的炎症和疼痛的临床体征有关。宿主防御和炎症过程中的神经元激活由G蛋白偶联受体（GPCR）介导的化学引诱物。白三烯B4（LTB 4）是一种对中性粒细胞有吸引力的化学物质，它激活其受体（BLT-1）介导中性粒细胞的多种生理效应。最近描述了具有不同拮抗剂特异性和组织分布的第二种LTB 4受体（BLT-2）。GPCR受受体磷酸化调节，导致脱敏以及下调。我们将检验LTB 4通过高亲和力受体BLT-1介导其对RA中性粒细胞的作用，而LTB 4通过BLT-2调节RA中T淋巴细胞活化和功能的假设。目前研究的目标是开发全面的体内和体外模型，以确定LTB 4的作用以及BLT-1和BLT-2在小鼠RA发展中的相对贡献。在具体目标1中，我们将定义BLT-1在我们已经通过靶向基因破坏产生的BLT-1缺陷小鼠中胶原诱导的关节炎的发展和进展中的作用。在具体目标2中，我们将使用完善的RBL-2 H3细胞模型来确定BLT-1和BLT-2的信号传导、脱敏、内化和拮抗剂特异性的差异。这些研究利用了我们最近开发的新型视频显微镜和活细胞成像方法。 白三烯参与了许多急性和慢性炎症性疾病的病理生理学，如全身性过敏反应、动脉粥样硬化、RA和哮喘。了解特定受体缺陷小鼠中不同LTB 4受体的确切功能并确定这些受体在RA中的作用将确定RA治疗干预的新靶点。

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.