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，其复杂的性质鲜为人知。这笔赠款 阐述了巨噬细胞通过几种不同的机制进入 血管壁可能起中介作用。首先，我们最近发现，一个 缺乏一种名为CD43的白细胞表面糖蛋白会导致 LDLR-/-小鼠的动脉粥样硬化。初步数据显示， CD43-/-小鼠动脉粥样硬化的减轻可能是由于 巨噬细胞迁移到病变，尽管这是不可能确定的 鉴于病变的进展性。因此，目标1将测试 CD43介导巨噬细胞进入病变部位的假说。迁移 CD43+/+或CD43-/-细胞在不同发育阶段进入皮损 接受检查。将对短期细胞迁移进行直接测量 使用培养的巨噬细胞。此外，在体外，细胞黏附/迁移 将被用来识别任何可能通过以下方式介导巨噬细胞运动的配体 与CD43结合。目标2将专注于另一种小鼠模型，在该模型中 选择素介导的白细胞黏附功能严重受损。这些老鼠缺乏一种 被称为岩藻糖基转移酶VII(Fuc-TVii)的酶，是 三种选择素(E、L和P)的配体合成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 动脉粥样硬化的内膜。我们还将确定以下哪些选择 相互作用对动脉粥样硬化的形成很重要。第三个目标围绕着一个 蛋白酪氨酸激酶，称为Fes，主要在髓系细胞中表达 细胞，对髓样细胞的发育很重要。Fes缺陷小鼠的表现 巨噬细胞黏附能力的显著缺陷。由于其 在动脉粥样硬化形成中的意义，FES缺乏将被研究与 病变发展。将使LDLR-/-小鼠Fes缺陷以确定 如果FES缺乏的巨噬细胞中的黏附缺陷会影响 动脉粥样硬化的发展。此外，短期体内迁移研究 利用来自Fes缺陷小鼠的巨噬细胞将揭示Fes缺陷 巨噬细胞在迁移到动脉粥样硬化部位时可能存在缺陷。这些 研究将提供有关巨噬细胞归巢到 损伤。此外，如果这些分子被证明是 巨噬细胞进入病变，可以设计出特定的治疗靶点。 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.