PHOSPHOLIPASE REGULATION OF MONOCYTE CHEMOTAXIS TO MCP-1

磷脂酶对单核细胞 MCP-1 趋化性的调节

• 批准号: 6767717
• 负责人: Martha K Cathcart
• 金额: $ 34.43万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6767717
• 关键词: arachidonate; biological signal transduction; chemotaxis; clinical research; enzyme activity; human tissue; laboratory mouse; monocyte; monocyte chemoattractant protein 1; phospholipase A2; phospholipase D

DESCRIPTION (provided by applicant): Monocytes are major participants in inflammatory responses and are mediators of chronic inflammation. Monocyte chemotactic factor 1 (MCP-1) is a critical chemotactic factor involved in attracting monocytes from the blood into tissues. This chemotactic cytokine has been shown to be a particularly important for the extravasation of monocytes into vessel walls in atherogenesis. Atherosclerosis-prone mice, when rendered deficient in either MCP-1 or its receptor, CCR2, develop significantly less atherosclerosis than their normal counterparts. Furthermore, MCP-1 has also been associated with a series of other chronic human inflammatory diseases including rheumatoid arthritis, viral meningitis, psoriasis, and inflammatory bowel disease. To date, we have a very cursory understanding of the signal transduction pathways regulating the chemotactic response of monocytes to MCP-I. In this application we propose experiments to elucidate the pathways regulating this central inflammatory process. Recent studies from our laboratory have identified a novel role for phospholipases A2 in regulating monocyte chemotaxis. When primary monocytes are rendered deficient in the expression of either cPLA2 or iPLA2 they fail to respond to the chemotactic stimulus of MCP-I. These pathways appear to operate independently in regulating the chemotactic response. It is clear that lipid signaling pathways are integral regulators of this monocyte chemotactic response. In this proposal we present a research plan to investigate how these PEA2 pathways regulate chemotaxis. In Aim 1 we will determine how these phospholipases relate to the few other pathways that have been identified in regulating MCP-l-induced monocyte chemotaxis and in the process we will explore the best approaches for selectively intervening in this process. We will examine the contributions of phospholipase D and AA metabolites in regulating chemotaxis and will explore the role of phospholipases in influencing cytoskeletal rearrangement and other cell processes involved in monocytic responses to MCP-1. These studies will significantly advance our understanding of this key inflammatory event.

描述（由申请人提供）：单核细胞是炎症反应的主要参与者，是慢性炎症的介体。单核细胞趋化因子1（MCP-1）是吸引血液中的单核细胞进入组织的关键趋化因子。这种趋化性细胞因子已被证明对于在动脉粥样硬化中单核细胞渗入血管壁特别重要。易动脉粥样硬化的小鼠，当MCP-1或其受体CCR2缺乏时，动脉粥样硬化明显少于其正常对应物。此外，MCP-1还与其他一系列慢性人类炎症性疾病有关，包括类风湿关节炎，病毒性脑膜炎，牛皮癣和炎症性肠病。迄今为止，我们对调节单核细胞对MCP-I的趋化反应的信号转导途径有非常粗略的了解。在此应用中，我们提出了实验，以阐明调节这种中心炎症过程的途径。我们实验室的最新研究确定了磷脂酶A2在调节单核细胞趋化性中的新作用。当原代单核细胞在CPLA2或IPLA2的表达中变得不足时，它们无法对MCP-I的趋化刺激做出反应。这些途径似乎在调节趋化反应方面独立运行。显然，脂质信号通路是该单核细胞趋化反应的积分调节剂。在此提案中，我们提出了一项研究计划，以研究这些PEA2途径如何调节趋化性。在AIM 1中，我们将确定这些磷脂酶与在调节MCP-L诱导的单核细胞趋化性方面已鉴定出的其他少数途径如何相关，在此过程中，我们将探讨选择性地介入此过程的最佳方法。我们将研究磷脂酶D和AA代谢产物在调节趋化性方面的贡献，并将探讨磷脂酶在影响细胞骨架重排和其他与MCP-1单核细胞反应有关的细胞过程中的作用。这些研究将大大提高我们对这一关键炎症事件的理解。