PHOSPHOLIPASE REGULATION OF MONOCYTE CHEMOTAXIS TO MCP-1

描述(申请人提供)：单核细胞是炎症反应的主要参与者，也是慢性炎症的媒介。单核细胞趋化因子1(MCP-1)是一种重要的趋化因子，参与将单核细胞从血液中吸引到组织中。这种趋化细胞因子在动脉粥样硬化形成中单核细胞渗入血管壁的过程中起着特别重要的作用。易患动脉粥样硬化的小鼠，当缺乏MCP-1或其受体CCR2时，比正常小鼠的动脉粥样硬化要少得多。此外，MCP-1还与其他一系列慢性人类炎症性疾病有关，包括类风湿性关节炎、病毒性脑膜炎、牛皮癣和炎症性肠病。到目前为止，我们对单核细胞对单核细胞趋化反应的信号转导途径的了解非常粗略。在这一应用中，我们建议进行实验来阐明调节这一中枢性炎症过程的途径。我们实验室最近的研究确定了磷脂酶A2在调节单核细胞趋化中的新作用。当原代单核细胞缺乏cPLA2或iPLA2的表达时，它们不能对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作。很明显，脂质信号通路是这种单核细胞趋化反应的不可或缺的调节因素。在这项提案中，我们提出了一项研究计划，以调查这些PEA2通路如何调节趋化作用。在目标1中，我们将确定这些磷脂酶与已发现的调控单核细胞趋化的少数其他途径之间的关系，并在此过程中探索选择性干预这一过程的最佳途径。我们将研究磷脂酶D和AA代谢产物在调节趋化作用中的作用，并将探索磷脂酶在影响细胞骨架重排和参与单核细胞对MCP-1反应的其他细胞过程中的作用。这些研究将极大地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.