M CSF AND THE PATHOGENESIS OF ATHEROSCLEROSIS

这项建议的长远目标是增加我们对 动脉粥样硬化的发病机制。 动脉粥样硬化病变中巨噬细胞集落水平升高 刺激因子(M-CSF或CSF-1)。正常人外周血中M-CSF的存在 动脉与动脉病变的增加相关，提示 巨噬细胞集落刺激因子可能在启动和/或 影响单核细胞-巨噬细胞噬菌体功能的动脉粥样硬化进展 以及动脉壁内的存活。我们之前的研究表明， 在动脉壁内局部部位诱导M-CSF的表达可能是 各种致动脉粥样硬化剂的伤害作用中的一个环节。这个 这些研究的总体目标是扩展我们的工作，使用 生物化学和分子遗传学方法研究 血管损伤诱导M-CSF表达的机制 并研究M-CSF通过的机制的各个方面 参与动脉粥样硬化的发病机制。具体目标 包括1)研究M-CSF对其自身表达的影响和 其受体等几种细胞因子的表达与生长 使用培养的人动脉壁细胞的因子，2)在体外使用 诱变和瞬时表达试验鉴定顺式作用 DNA元件在血管损伤中的作用 人M-CSF基因的上调；3)检测M-CSF顺式作用DNA 与特定核蛋白结合的元件和鉴定反式- 参与血管损伤的作用因素 转录激活，4)利用小鼠动脉损伤模型 检测M-CSF及其受体在体内的诱导表达，以及5) 为探讨M-CSF对动脉病变生长的影响。 体内使用骨质疏松(OP/OP)小鼠的相关细胞 缺乏M-CSF和载脂蛋白E(ApoE)缺陷的小鼠表现出 加速动脉粥样硬化。拟议的实验将提供 重要信息有助于我们更好地理解 巨噬细胞集落刺激因子在动脉粥样硬化发病机制中的作用 开发控制这种疾病的方法。

The long range goal of this proposal is to increase our understanding of the mechanisms involved in the pathogenesis of atherosclerosis. Atherosclerotic lesions contain elevated levels of macrophage-colony stimulating factor (M-CSF or CSF-1). The presence of M-CSF in the normal artery correlates with an increase in the arterial lesion suggesting that M-CSF may contribute significantly to the initiation and/or progression of atherosclerosis by affecting monocyte-mac ophage function and survival in the artery wall. Our previous studies indicate that induced expression of M-CSF at focal sites within the artery wall may be one link among the injurious effects of various atherogenic agents. The overall objectives of these studies are to extend our work using combined biochemical and molecular genetic approaches to investigate the mechanisms involved in the vascular injury-induced expression of M-CSF, and to examine the aspects of the mechanisms through which M-CSF participates in the pathogenesis of atherosclerosis. The specific aims include 1) to investigate the effects of M-CSF on its own expression and the expression of its receptor and several other cytokines and growth factors using cultured human artery wall cells, 2) to use in vitro mutagenesis and transient expression assays to identify the cis-acting DNA elements involved in the vascular injury-induced or autoinduced upregulation of the human M-CSF gene, 3) to test the M-CSF cis-acting DNA elements for binding to specific nuclear proteins and identify trans- acting factors that participate in the vascular injury-mediated transcriptional activation, 4) to use mouse model of arterial injury to examine the induced expression of M-CSF and its receptor in vivo, and 5) to investigate the effects of M-CSF ont he growth of arterial lesion- associated cells in vivo using osteopetrotic (op/op) mice that totally lack M-CSF and apolipoprotein E (apoE)-deficient mice that exhibit accelerated atherosclerosis. The proposed experiments will provide important information that will enhance our understanding of the role of M-CSF in the pathogenesis of atherosclerosis, and may prove valuable in developing ways to control the disease.