CELLULAR VITAMIN E STATUS AND INTEGRIN FUNCTION

这一建议是基于一种假设，即白细胞和 血小板维生素E含量是血管炎症的重要决定因素 通过其对β2和β3整合素功能的作用。这一假设是 重要的是因为实验、临床和病理研究 确立了炎症在动脉粥样硬化等血管疾病中的作用 以及对动脉损伤的反应。炎性细胞-细胞和细胞基质 相互作用是由细胞黏附分子协调的，相当大 实验工作证明，血管细胞之间的平衡 抗氧化剂状态和氧化应激参与调节 血管细胞黏附分子。然而，抗氧化剂状态对 这些血管细胞的白细胞和血小板整合素受体 黏附分子在很大程度上被忽视了。来自我们的初步数据 实验室表明，维生素E有效地抑制了β2的功能 单核细胞中的整合素和血小板中的β3整合素。这样做的目的是 因此，建议定义细胞维生素E的作用，这是主要的 人体脂溶抗氧化剂对白细胞整合素功能的影响 血小板。这一提议的主要实验模型将被培养 人单核细胞(U937和THP-1)和中性粒细胞以及新鲜的 分离的人类血小板。为了实现这个项目的目标，我们将完成 维生素E对β2整合素依赖的抑制作用特征 使用与血管疾病相关的激动剂进行单核细胞黏附，包括 氧化剂。这一特征将扩展到人类中性粒细胞和 血小板，两种重要的血管炎症介质和对血管炎症的反应 受伤。一旦确定了这一特征，调查人员将 研究主要关注细胞内钙离子的候选机制 瞬时和蛋白激酶C磷酸化状态，维生素E的两个靶点 在我们的初步数据中确定了。最后，私人投资总监将建立 通过测试维生素E的活性来研究他们的发现的生理学相关性 一种新开发的小鼠的血管炎症和新生内膜生长 我们已经建立的依赖于血小板的动脉损伤模型 沉积和β2整合素功能。总的来说，这些研究应该 阐明了血管炎症的控制，并提供了见解 有必要设计重要的血管调节新策略 疾病是当今世界发病率和死亡率的一个重要来源。

This proposal is based upon the hypothesis that leukocyte and platelet vitamin E content is an important determinant of vascular inflammation through its action on beta 2 and beta 3 integrin function. This hypothesis is important because experimental, clinical and pathologic studies have established a role for inflammation in vascular disease such as atherosclerosis and the response to arterial injury. Inflammatory cell-cell and cell-matrix interactions are orchestrated by cell adhesion molecules and considerable experimental effort has demonstrated that the balance between vascular cell antioxidant status and oxidative stress is involved in the regulation of vascular cell adhesion molecules. However, the effect of antioxidant status on leukocyte and platelet integrin counter-receptors for these vascular cell adhesion molecules has been largely overlooked. Preliminary data from our laboratories indicates that vitamin E potently inhibits the function of beta 2 integrins in monocytes and beta 3 integrins in platelets. The goal of this proposal, therefore, is to define the role of cellular vitamin E, the principal lipid-soluble antioxidant in humans, on integrin function in leukocytes and platelets. The primary experimental models for this proposal will be cultured human monocytic cells (U937 and THP-1) and neutrophils, as well as freshly isolated human platelets. To achieve the goal of this project, we will finish characterizing inhibitor action of vitamin E on beta 2 integrin-dependent monocyte adhesion using agonists relevant to vascular disease including oxidants. The characterization will be extended to human neutrophils and platelets, two important mediators of vascular inflammation and the response to injury. Once this characterization is established, the investigators will investigate candidate mechanisms focusing primarily on intracellular calcium transients and protein kinase C phosphorylation status, two vitamin E targets identified in our preliminary data. Finally, the PIs will establish the physiologic relevance of their findings by testing the activity of vitamin E on vascular inflammation and neointimal growth using a newly developed murine model of arterial injury that we have established to be dependent on platelet deposition and beta 2 integrin function. Collectively, these studies should shed light on the control of vascular inflammation and provide the insights necessary to design important new strategies for the modulation of vascular disease, an important source of morbidity and mortality in the world today.