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。 前列腺素是由动脉壁中的内皮细胞、单核细胞/巨噬细胞和平滑肌细胞产生的重要炎症介质。 环氧合酶（考克斯）是花生四烯酸合成前列腺素的限速酶。 考克斯存在于两种亚型中，即考克斯-1和考克斯-2，它们由两个独立的基因编码。 考克斯-1在大多数组织中组成型表达，介导细胞的“管家”功能。 相反，考克斯-2表达在大多数组织中通常检测不到，但其表达在炎症期间被多种试剂（包括细胞因子和生长因子）快速诱导。考克斯-2在动脉粥样硬化病变中表达，提示其可能在动脉粥样硬化的炎症介导中起重要作用。 在具体目标1中，我们将检验通过选择性抑制考克斯-2抑制apoE缺陷小鼠的炎症过程将导致动脉粥样硬化减少的假设。 靶向破坏考克斯-1和考克斯-2基因的小鼠的可用性为研究这些基因对动脉粥样硬化的贡献提供了强有力的工具。 在具体目标2中，我们将检验考克斯-2基因表达缺失的小鼠将免受动脉粥样硬化的假设。 考克斯-2由血管系统中的几种细胞表达，包括内皮、平滑肌和巨噬细胞。 考克斯-2缺陷小鼠的骨髓移植研究提供了一种解剖出巨噬细胞表达考克斯-2在动脉粥样硬化中的作用的方法。这些研究将为考克斯-1和考克斯-2在动脉粥样硬化中的表达提供新的生理相关性。 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.