CCR2 in Atherosclerosis and Leukocyte Trafficking

描述(申请人提供)：单核细胞和巨噬细胞的运输在动脉粥样硬化、对细胞内病原体的抵抗和抗原呈递中起着关键作用，但调节这种运输的信号还不是很清楚。本应用的总体目标是阐明趋化因子受体2(CCR2)，单核细胞趋化蛋白(MCPs)的受体在维持动脉粥样硬化病变、抵抗细胞内病原体以及在1型(THL)极化免疫反应发展中的作用。在这笔赠款的前两个资金周期中，我们克隆了CCR2，并表明CCR2-/-小鼠比野生型小鼠患上的动脉粥样硬化更少。在目前的应用中，我们将扩展这些发现，并将使用新创建的人CCR2敲入小鼠来测试CCR2拮抗剂将消退动脉粥样硬化病变的假设。我们将在野生型和CCR2-/-小鼠之间移植主动脉节段，以提供第二种独立的方法来评估CCR2在病变消退中的作用。在这一应用中的实验将利用一种新的报告基因在转基因小鼠中的条件表达系统来获得从简单到复杂病变的巨噬细胞外流的动力学信息。我们团队和其他人的工作表明，CCR2-/-小鼠产生干扰素伽马的能力明显受损，这可能与它们对细胞内病原体的易感性有关。我们将使用CCR2-/-和MCP-I-/-小鼠来阐明这种细胞因子产生缺陷的基础。我们新创建的MCP-5-/-小鼠的最新结果表明，在该模型中，MCP-1将细胞吸引到免疫/感染部位，而MCP-5将细胞引导到引流淋巴结。我们将扩展这些研究，并检验MCP家族中不同成员的趋化因子在不同组织中优先表达的假设。完成这笔赠款的具体目标将提供关于CCR2在动脉粥样硬化病变的维持和消退、抗原提呈细胞的运输和极化T细胞反应的发展中的作用的新数据。这些数据将直接说明CCR2拮抗剂的治疗前景。

DESCRIPTION (provided by applicant): Trafficking of monocytes and macrophages plays a critical role in atherosclerosis, resistance to intracellular pathogens, and antigen presentation, but the signals that regulate this trafficking are not well understood. The overall goal of this application is to elucidate the role of chemokine receptor 2 (CCR2), the receptor for the monocyte chemoattractant proteins (MCPs) in maintenance of atherosclerotic lesions, in resistance to intracellular pathogens, and in the development of type 1 (Thl) polarized immune responses. During the first two funding cycles of this grant we have cloned CCR2, and shown that CCR2 -/- mice develop less atherosclerosis than wild-type littermate controls. In the current application we will extend those findings, and will use newly created human CCR2 knock-in mice to test the hypothesis that CCR2 antagonists will regress atherosclerotic lesions. We will transplant segments of the aorta between wild-type and CCR2 -/- mice to provide a second, independent method for evaluating the role of CCR2 in lesion regression. Experiments in this application will utilize a novel system of conditional expression of reporter genes in transgenic mice to obtain kinetic information on macrophage efflux from simple to complex lesions. Work from our group and others has shown that CCR2-/- mice have a marked impairment in their ability to make interferon gamma, and this may contribute to their susceptibility to intracellular pathogens. We will use CCR2-/- and MCP-I -/- mice to elucidate the basis for this cytokine production defect. Recent results from our newly created MCP-5 -/- mice suggest a model in which MCP-1 attracts cells to the site of immunization/infection, and MCP-5 directs cells to the draining lymph node. We will extend those studies, and test the hypothesis that different members of the MCP-family of chemokines are preferentially expressed in different tissues. Completion of the specific aims of this grant will provide new data on the role of CCR2 in the maintenance and regression of atherosclerotic lesions, and in the trafficking of antigen presenting cells and the development of polarized T cell responses. This data will speak directly to the therapeutic prospects for CCR2 antagonists.