M CSF AND THE PATHOGENESIS OF ATHEROSCLEROSIS

这项提案的长期目标是增加我们对以下问题的了解： 动脉粥样硬化的发病机制。 动脉粥样硬化病变含有高水平的巨噬细胞集落 刺激因子（M-CSF或CSF-1）。M-CSF在正常人中的存在 动脉与动脉病变的增加相关， M-CSF可能对启动和/或 通过影响单核细胞-巨噬细胞功能而进展动脉粥样硬化 以及在动脉壁中存活的能力我们之前的研究表明， 在动脉壁内的病灶部位诱导M-CSF表达可能是 各种致动脉粥样硬化剂的有害作用之间的一个联系。的 这些研究的总体目标是扩展我们的工作， 生物化学和分子遗传学方法来研究 涉及血管损伤诱导的M-CSF表达的机制， 并检查M-CSF通过其机制的各个方面， 参与动脉粥样硬化的发病机制。具体目标 包括1）研究M-CSF对自身表达的影响， 其受体和其他几种细胞因子的表达和生长 使用培养的人动脉壁细胞的因子，2）体外使用 突变和瞬时表达测定来鉴定顺式作用的 血管损伤诱导或自身诱导的DNA元件 人M-CSF基因的上调，3）测试M-CSF顺式作用DNA 元件结合到特定的核蛋白，并确定反式- 参与血管损伤介导的作用因子 转录激活，4）使用小鼠动脉损伤模型， 检查体内M-CSF及其受体的诱导表达，和5） 研究M-CSF对动脉病变生长的影响， 相关细胞在体内使用骨硬化症（OP/OP）小鼠， 缺乏M-CSF和载脂蛋白E（apoE）的小鼠， 加速动脉粥样硬化这些实验将提供 重要的信息，这将提高我们的理解的作用， M-CSF在动脉粥样硬化发病机制中的作用， 开发控制疾病的方法。

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.