Leukotriene B4 Receptors in Rheumatoid Arthritis

类风湿关节炎中的白三烯 B4 受体

• 批准号: 6610703
• 负责人: HARIBABU BODDULURI
• 金额: $ 27.01万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6610703
• 关键词: cell surface receptors; chemotaxis; confocal scanning microscopy; gene targeting; genetically modified animals; inflammation; laboratory mouse; leukocyte activation /transformation; leukotrienes; membrane activity; neutrophil; pathologic process; protein structure function; receptor sensitivity; rheumatoid arthritis; video microscopy

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.

描述（由申请人提供）：类风湿关节炎（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，并被认为与与RA相关的炎症和疼痛的临床迹象有关。宿主防御和炎症期间的中性粒细胞激活是由G蛋白偶联受体（GPCR）用于趋化剂的。白细胞B4（LTB4），一种有效的嗜中性粒细胞的趋化性趋化剂可激活其受体（BLT-1），以介导中性粒细胞中各种生理作用。最近描述了具有不同拮抗剂特异性和组织分布的第二个LTB4受体（BLT-2）。 GPCR受受体磷酸化调节，导致脱敏和下调。我们将检验以下假设：通过高亲和力受体BLT-1作用的LTB4介导了其对RA中嗜中性粒细胞的影响，而通过BLT-2作用的LTB4调节T-淋巴细胞激活和RA中的功能。当前研究的目的是开发体内和体外模型的全面，以确定LTB4的作用以及BLT-1和BLT-2在Murine RA开发中的相对贡献。在特定目标1中，我们将定义BLT-1在胶原蛋白诱导的关节炎的发育和进展中的作用，在BLT-1缺乏小鼠中，我们已经通过靶向基因破坏产生的。在特定目标2中，我们将使用良好的RBL-2H3细胞模型来确定BLT-1和BLT-2的信号传导，脱敏，内在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。 白细胞参与许多急性和慢性炎性疾病的病理生理，例如全身性过敏反应，动脉粥样硬化，RA和哮喘。了解在特定受体缺乏的小鼠中不同的LTB4受体的精确功能，并定义这些受体在RA中的作用将确定RA治疗干预的新靶标。