PHOSPHOLIPASE REGULATION OF MONOCYTE CHEMOTAXIS TO MCP-1

描述（由申请人提供）：单核细胞是炎症反应的主要参与者，是慢性炎症的介质。单核细胞趋化因子1（MCP-1）是一种重要的趋化因子，参与将血液中的单核细胞吸引到组织中。这种趋化性细胞因子已被证明是一个特别重要的外渗单核细胞进入血管壁的动脉粥样硬化。当MCP-1或其受体CCR 2缺乏时，易患动脉粥样硬化的小鼠比正常小鼠发生动脉粥样硬化的程度要低得多。此外，MCP-1还与一系列其他慢性人类炎性疾病相关，包括类风湿性关节炎、病毒性脑膜炎、银屑病和炎性肠病。到目前为止，我们对调节单核细胞对MCP-1趋化反应的信号转导途径有一个非常粗略的了解。在这个应用程序中，我们提出的实验来阐明调节这一中枢炎症过程的途径。我们实验室最近的研究已经确定了磷脂酶A2在调节单核细胞趋化性中的新作用。当使原代单核细胞缺乏cPLA 2或iPLA 2的表达时，它们不能响应MCP-1的趋化刺激。这些途径似乎独立地调节趋化反应。很明显，脂质信号通路是这种单核细胞趋化反应的整体调节剂。在这个提议中，我们提出了一个研究计划，以调查这些PEA 2途径如何调节趋化性。在目标1中，我们将确定这些磷脂酶如何与在调节MCP-1诱导的单核细胞趋化性中已经鉴定的少数其他途径相关，并且在该过程中，我们将探索选择性干预该过程的最佳方法。我们将研究磷脂酶D和AA代谢产物在调节趋化性中的作用，并将探讨磷脂酶在影响细胞骨架重排和单核细胞对MCP-1反应的其他细胞过程中的作用。这些研究将大大促进我们对这一关键炎症事件的理解。

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.