Leukocyte C2GIcNAcT-I in atherosclerosis

描述(申请人提供)：动脉粥样硬化及其并发症是导致发病率和死亡率的最常见原因。这些血管疾病是白细胞、血小板和管壁细胞之间黏附和信号相互作用的结果。这些细胞相互作用是由黏附分子介导的，包括P、E、L-选择素、P-选择素糖蛋白配体1、CD43、CD44、整合素CD18、VLA-4等。这些分子介导的细胞相互作用广泛参与动脉粥样硬化的各种事件。为了获得最佳的活性，包括PSGL-1、CD43和CD44在内的分子需要通过在其蛋白质结构中添加支化的O-糖链来修饰。这些反应是由核心2 1-6-N-氨基葡萄糖转移酶-L(C2GlcNAcT-L)催化的，它是白细胞中的一种高尔基酶。该项目旨在研究C2GlcNAcT-L是否在动脉粥样硬化及其并发症的发生发展过程中的细胞相互作用中起关键作用。在目标1中，我们将研究C2GlcNAcT-L在单个核细胞与动脉粥样硬化的相互作用中的作用。在目的2中，我们将探讨C2GlcNAcT-L在活化的血小板在动脉粥样硬化中的作用。在目标3中，我们将探讨C2GlcNAcT-L在动脉粥样硬化病变的发生、发展和消退中的作用。我们还将评估C2GlcNAcT-L对动脉粥样硬化病变稳定性的影响。目的4通过建立小鼠颈总动脉损伤模型，研究C2GlcNAcT-L在白细胞和血小板与损伤动脉的相互作用以及在动脉新生内膜形成中的作用。这些研究将对抑制白细胞C2GlcNAcT-L防治动脉粥样硬化及其并发症具有重要意义。

DESCRIPTION (provided by applicant): Atherosclerosis and its complications are the most common causes of morbidity and mortality. These vascular diseases result from adhesive and signaling interactions among leukocytes, platelets and the vessel wall cells. These cellular interactions are mediated by adhesion molecules, including P, E, L-selectin, P-selectin glycoprotein ligand 1 (PSGL-1), CD43, CD44, integrin CD18, VLA-4, and others. The cellular interactions mediated by these molecules broadly participate in various events in atherosclerosis. To obtain optimal activities, molecules including PSGL-1, CD43 and CD44 need to be modified by the addition of branched O-glycans to their protein structures. These reactions are catalyzed by core 2 1-6-N- glucosaminyltransferase-l (C2GlcNAcT-l), which is a Golgi enzyme in leukocytes. This project is designed to investigate whether C2GlcNAcT-l is crucial for cellular interactions involved in the development of atherosclerosis and its complications. In aim 1, we will investigate the rote of C2GlcNAcT-l in the interactions of mononuclear cells with atherosclerotic arteries. In aim 2, we will investigate the role of C2GlcNAcT-l in the contribution of activated platelets to atherosclerosis. In aim 3, we will investigate the role of C2GlcNAcT-l in the development, progression and regression of atherosclerotic lesions. We will also evaluate the influence of C2GlcNAcT-l in the stability of atherosclerotic lesions. In aim 4, we will investigate the role of C2GlcNAcT-l in the interactions of leukocytes and platelets with injured arteries and in the formation of arterial neointima using an established mouse carotid artery wire injury model. These studies will have significant implications for the inhibition of leukocyte C2GlcNAcT-l in the prevention and treatment of atherosclerosis and its complications.