Application of gene targeting to the study of atherosclerosis

基因打靶在动脉粥样硬化研究中的应用

• 批准号: 05404033
• 负责人: YAZAKI Yoshio
• 金额: $ 14.78万
• 依托单位: University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (A)
• 财政年份: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1994
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-05404033/
• 关键词: Ahterosclerosis; Endothekial cells; Smooth muscle cell; Macrophage; Gene targeting; Cholesterol; Bllod pressure; Scavenger receptor; ジーンターゲティング; トランスジェニックマウス; 形態形成; 血圧調節; 病態生理

In order to elucidate the role of multiple genetic factors on the process of atherosclerosis, we used the mouse developmental biological technics, especially gene targeting using homologous recombination in ES cells. We established the endothelin-1 knockout mice, macrophage scavenger receptor knockout mouse, and other gene targeted mice strains in order to analyze the roles of these genes, and the mechanism how endothelial cells, smooth muscle cells and macrophages are involved in the atherogenesis. The heterozygout mice deficient in endothekin-1 indicated the increase of blood pressure. Macrophage obtained from the homozygout for scavenger receptor deficiency indicated the marked decrease in both acetyl-LDL degradation and oxidized LDL degradation. Adding to this, these macrophage also indicated the decrease in the binding activity of both AGE and LPS.The function of these genes in vivo is different from those studied in vitro, and mouse developmental biological technics, especially gene targeting provide a nice tool to analyze these problems.

为了阐明多种遗传因素在动脉粥样硬化过程中的作用，我们采用小鼠发育生物学技术，特别是在胚胎干细胞中采用同源重组的基因靶向。我们建立了内皮素-1敲除小鼠、巨噬细胞清道夫受体敲除小鼠等基因靶向小鼠品系，分析这些基因的作用，以及内皮细胞、平滑肌细胞和巨噬细胞参与动脉粥样硬化的机制。内皮素-1缺失的杂合子小鼠血压升高。清除受体缺乏症纯合子获得的巨噬细胞表明乙酰-LDL降解和氧化LDL降解均显著降低。此外，这些巨噬细胞还显示AGE和LPS的结合活性降低。这些基因在体内的功能与在体外研究的不同，而小鼠发育生物学技术，特别是基因靶向技术为分析这些问题提供了很好的工具。

项目成果

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Yukiko Kurihara 和其他 16 人：“小鼠内皮素 1 基因的破坏”（出版中）。

Maemura K,Yazaki Yet al.: "Renal endothelin and hypertension-reply." Nature. 372. 50 (1994)

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江見充 他12名: "Structure,organization,and chromosomal mapping of the human macrophage scavenger receptor gene." J.Biol.Chem.268. 2120-2125 (1993)

Mitsuru Emi 和其他 12 人：“人类巨噬细胞清道夫受体基因的结构、组织和染色体图谱”，J.Biol.Chem.268（1993）。

Kurihara Y,yazaki Y et al.: "Elevated blood pressure and craniofacial abnormalities in mice deficient in endothelin-1" Nature. 368. 703-710 (1994)

Kurihara Y、yazaki Y 等人：“缺乏内皮素-1 的小鼠血压升高和颅面异常”《Nature》。