BONE MARROW TRANSPLANTATION AND ATHEROSCLEROSIS

越来越多的证据支持动脉粥样硬化是一种慢性炎症性疾病的观点。前列腺素是重要的炎症介质，由动脉壁内皮细胞、单核/巨噬细胞和平滑肌细胞产生。环氧合酶(COX)是花生四烯酸合成前列腺素的限速酶。COX以COX-1和COX-2两种亚型存在，由两个不同的基因编码。COX-1在大多数组织中有结构性表达，参与细胞的“管家”功能。相反，COX-2的表达通常在大多数组织中检测不到，但在炎症过程中，它的表达会被包括细胞因子和生长因子在内的各种因素迅速诱导。COX-2在动脉粥样硬化病变中有表达，提示COX-2可能在动脉粥样硬化的炎症反应中发挥重要作用。在特定的目标1中，我们将检验这样的假设，即通过选择性地抑制COX-2来抑制载脂蛋白E缺陷小鼠的炎症过程将导致动脉粥样硬化的减轻。靶向阻断COX-1和COX-2基因的小鼠的可获得性，为研究这些基因在动脉粥样硬化中的作用提供了有力的工具。在特定的目标2中，我们将检验COX-2基因表达缺失的小鼠将受到动脉粥样硬化保护的假设。COX-2由血管内皮细胞、平滑肌细胞和巨噬细胞等多种细胞表达。对COX-2基因缺陷小鼠的骨髓移植研究为剖析巨噬细胞表达COX-2在动脉粥样硬化中的作用提供了一条途径。建议的研究将为动脉粥样硬化中COX-1和COX-2的表达在体内的生理相关性提供新的见解。通过进一步了解炎症在动脉粥样硬化中的作用，这些研究可能为预防动脉粥样硬化的新的治疗方法提供理论基础。

Mounting evidence supports the view that atherosclerosis is a chronic inflammatory disease, process. Prostaglandins are important mediators of inflammation that are produced by endothelial cells, monocyte/macrophages, and smooth muscle cells in the artery wall. Cyclooxygensae (COX) is the rate-limiting enzyme in the production of PGs from arachidonic acid. COX exists in two isoforms, COX-1 and COX-2, that are encoded by two separate genes. COX-1 is constitutively expressed in most tissues mediating "housekeeping" functions of the cells. In contrast, COX-2 expression is normally not detectable in most tissues but its expression is rapidly induced during inflammation by a variety agents, including cytokines and growth factors. COX-2 is expressed in atherosclerotic lesions suggesting that it may play an important role in mediating inflammation in atherosclerosis. In Specific Aim 1, we will examine the hypothesis that inhibition of the inflammatory process in apoE deficient mice by selective inhibition of COX-2 will result in decreased atherosclerosis. The availability of mice with targeted disruption of the genes for COX-1 and COX-2, provides a powerful tool to investigate the contributions of these genes to atherosclerosis. In Specific Aim 2, we will examine the hypothesis that mice null for COX-2 gene expression will be protected from atherosclerosis. COX-2 is expressed by several cells in the vasculature, including endothelium, smooth muscle, and macrophages. Bone marrow transplantation studies in COX-2 deficient mice provides an approach for dissecting out the contribution of macrophage expression of COX-2 in atherosclerosis. The proposed studies should provide new insights into the physiological relevance in vivo of COX-1 and COX-2 expression in atherosclerosis. By furthering our understanding of the role of inflammation in atherosclerosis, these studies may provide the rationale for new therapeutic approaches to the prevention of atherosclerosis.