Macrophage migration in atherosclerosis

描述（由申请人提供）： 巨噬细胞进入动脉壁是动脉粥样硬化的重要组成部分 动脉粥样硬化，其复杂的性质知之甚少。这笔赠款 解决了几种不同的机制，巨噬细胞进入 血管壁可能是介导的。首先，我们最近发现， 一种称为CD 43的白细胞表面糖蛋白的缺乏导致 LDLR-/-小鼠的动脉粥样硬化。初步数据显示， CD 43-/-小鼠动脉粥样硬化的减少可能是由于受损的 巨噬细胞迁移到病变，尽管这是不可能确定的 鉴于病变的严重程度因此，目标1将测试 假设CD 43介导巨噬细胞进入病变部位。迁移 CD 43 +/+或CD 43-/-细胞在不同发育阶段进入病变， 接受检查。将直接测量短期细胞迁移 使用培养的巨噬细胞。此外，体外细胞粘附/迁移 将用于鉴定任何可能介导巨噬细胞运动的配体， 与CD 43结合。Aim 2将关注另一种小鼠模型， 选择素介导的白细胞粘附被大大削弱。这些老鼠缺乏 一种叫做岩藻糖基转移酶VII（Fuc-TVII）的酶， 合成所有3种（E、L和P）选择素的配体。Fuc-TVII-/-小鼠将 与易患动脉粥样硬化的LDLR-/-小鼠杂交，以确定 巨噬细胞利用选择素-配体相互作用进入细胞内， 动脉粥样硬化内膜我们还将确定哪些选择 相互作用对于动脉粥样硬化形成是重要的。第三个目标围绕着一个 一种称为Fes的蛋白酪氨酸激酶，主要在骨髓中表达 细胞，对骨髓发育很重要。Fes展示缺陷小鼠 巨噬细胞粘附能力的显著缺陷。由于其 在动脉粥样硬化形成的影响，Fes缺乏症将研究与 病变发展将使LDLR-/-小鼠缺乏Fes，以确定 如果Fes缺陷巨噬细胞的粘附缺陷会影响 动脉粥样硬化发展。此外，短期体内迁移研究 与来自Fes缺陷小鼠的巨噬细胞进行比较， 巨噬细胞可能在迁移到动脉粥样硬化部位方面有缺陷。这些 研究将提供关于巨噬细胞归巢到 病变此外，如果这些分子被证明是必不可少的， 巨噬细胞进入病变，可以设计特定的治疗靶点 通过抑制巨噬细胞迁移来对抗动脉粥样硬化。

DESCRIPTION (provided by applicant): Macrophage entry into the artery wall is an essential component of atherosclerosis whose complex nature is poorly understood. This grant addresses several different mechanisms by which macrophage entry into the vessel wall may be mediated. First, we have discovered recently that a deficiency of a leukocyte surface glycoprotein called CD43 results in reduced atherosclerosis in LDLR-/- mice. Preliminary data indicated that the reduction in atherosclerosis in the CD43-/- mice may be due to impaired macrophage migration to the lesion, although this is impossible to ascertain given the advanced nature of the lesions. Thus, aim 1 will test the hypothesis that CD43 mediates entry of macrophages to lesion sites. Migration of CD43+/+ or CD43-/- cells into lesions at various developmental stages will be examined. Direct measurement of short-term cell migration will be made using cultured macrophages. In addition, in vitro cell adhesion/migration will be used to identify any ligands that might mediate macrophage movement by binding to the CD43. Aim 2 will focus on another model of mice in which selectin-mediated leukocyte adhesion is greatly impaired. These mice lack an enzyme called fucosyltransferase VII (Fuc-TVII) that is essential for synthesis of ligands for all 3 (E, L and P) selectins. Fuc-TVII-/- mice will be crossed with the atherosclerosis-prone LDLR-/- mice to determine if macrophages utilize the selectin-ligand interaction to enter the atherosclerotic intima. We will also determine which of the selectin interactions is important for atherogenesis. The third aim revolves around a protein tyrosine kinase called Fes that is expressed primarily in myeloid cells and is important for myeloid development. Mice deficient in Fes display a striking defect in the ability of their macrophages to adhere. Due to its implications in atherogenesis, Fes deficiency will be studied in relation to lesion development. LDLR-/- mice will be made deficient in Fes to determine if the adherence defect in the Fes deficient macrophages will affect atherosclerotic development. In addition short term in vivo migration study with macrophages from Fes deficient mice will reveal if Fes deficient macrophages may be defective in migrating to atherosclerotic sites. These studies will provide much needed information about macrophage homing to the lesions. Moreover, if these molecules are shown to be essential for macrophage entry into the lesion, specific therapeutic targets can be devised to combat atherosclerosis by inhibiting macrophage migration.