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BONE MARROW TRANSPLANTATION AND ATHEROSCLEROSIS

骨髓移植和动脉粥样硬化

基本信息

批准号：
6606193
负责人：
MACRAE F LINTON
金额：
$ 37.75万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-05-01 至 2004-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6606193
关键词：
apolipoprotein E atherosclerosis blood lipoprotein metabolism bone marrow transplantation cholesterol genetic markers genetic strain laboratory mouse low density lipoprotein macrophage remission /regression

项目摘要

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.

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过程的观点。前列腺素是动脉壁内皮细胞、单核细胞/巨噬细胞和平滑肌细胞产生的重要炎症介质。环加氧酶 (COX) 是花生四烯酸生产 PG 的限速酶。 COX 存在两种同工型：COX-1 和 COX-2，由两个独立的基因编码。 COX-1 在大多数组织中组成型表达，介导细胞的“管家”功能。相比之下，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，多种因子（包括细胞因子和生长因子）会迅速诱导其表达。 COX-2在动脉粥样硬化病变中表达，表明它可能在介导动脉粥样硬化炎症中发挥重要作用。在具体目标 1 中，我们将检验以下假设：通过选择性抑制 COX-2 来抑制 apoE 缺陷小鼠的炎症过程，从而减少动脉粥样硬化。靶向破坏 COX-1 和 COX-2 基因的小鼠的出现，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。在具体目标 2 中，我们将检验这样的假设：COX-2 基因表达缺失的小鼠将免受动脉粥样硬化的影响。 COX-2 由脉管系统中的多种细胞表达，包括内皮细胞、平滑肌和巨噬细胞。 COX-2 缺陷小鼠的骨髓移植研究提供了一种剖析 COX-2 巨噬细胞表达在动脉粥样硬化中的作用的方法。拟议的研究应该为动脉粥样硬化中 COX-1 和 COX-2 表达的体内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基础。

项目成果

期刊论文数量（28）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Isoform-specific effects of apolipoprotein E on atherogenesis: gene transduction studies in mice.

载脂蛋白 E 对动脉粥样硬化形成的异构体特异性影响：小鼠基因转导研究。

DOI：
10.1161/hc4801.100034
发表时间：
2001
期刊：
Circulation
影响因子：
37.8
作者：
Yoshida,H;Hasty,AH;Major,AS;Ishiguro,H;Su,YR;Gleaves,LA;Babaev,VR;Linton,MF;Fazio,S
通讯作者：
Fazio,S

Macrophages, lipoprotein metabolism, and atherosclerosis: insights from murine bone marrow transplantation studies.

巨噬细胞、脂蛋白代谢和动脉粥样硬化：来自小鼠骨髓移植研究的见解。