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，由内皮细胞、单核/巨噬细胞和动脉壁平滑肌细胞产生。环氧合酶（COX）是花生四烯酸生产pg的限速酶。COX存在于COX-1和COX-2两种同工异构体中，由两个独立的基因编码。COX-1在大多数组织中组成性表达，介导细胞的“管家”功能。相比之下，COX-2的表达在大多数组织中通常是检测不到的，但在炎症期间，它的表达会被多种因子（包括细胞因子和生长因子）迅速诱导。COX-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中介导炎症发挥重要作用。在Specific Aim 1中，我们将检验通过选择性抑制COX-2抑制apoE缺陷小鼠炎症过程将导致动脉粥样硬化减少的假设。有针对性地破坏COX-1和COX-2基因的小鼠，为研究这些基因对动脉粥样硬化的贡献提供了有力的工具。在Specific Aim 2中，我们将检验COX-2基因表达缺失的小鼠免受动脉粥样硬化的假设。COX-2在多种血管细胞中表达，包括内皮细胞、平滑肌细胞和巨噬细胞。COX-2缺陷小鼠的骨髓移植研究为揭示巨噬细胞表达COX-2在动脉粥样硬化中的作用提供了一种途径。提出的研究应该为体内COX-1和COX-2表达在动脉粥样硬化中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治疗方法提供理论依据。

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.