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Establishment of animal models for atheroscherosis and gene therapy

动脉粥样硬化动物模型的建立及基因治疗

基本信息

批准号：
05557049
负责人：
YAMADA Nobuhiro
金额：
$ 9.79万
依托单位：
University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Developmental Scientific Research (B)
财政年份：
1993
资助国家：
日本
起止时间：
1993 至 1995
项目状态：
已结题

项目摘要

In the transgenic mouse or knockout mouse, a specific gene can be transduced or deleted to study its function and relation to human diseases. Recently, various lines of transgenic mice or knockout mice which overexpress or lack a specific gene have been established and are available to study the pathophysiology of human diseases, including atherosclerosis, diabetes mellitus, and hyperlipidemia. We have established transgenic mouse lines with an integrated rat apoE gene and human lipoprotein lipase gene. Overexpression of apoE reduced plasma cholesterol and triglycerides levels, and prevented diet induced hypercholesterolemia. Another transgenc model with overexpression of apoE under control of the H2 Ld promoter in the arterial wall was established. In this model, the formation of fatty streak lesions was markedly inhibited, suggesting that apoE has anti-atherogenic actions. To establish new animal models for atherosclerosis, transgenic mice overexpressing lipoprotein lipase were crossbred with LDL receptor knockout mice. Overexpression of lipoprotein lipase markedly reduced plasma remnant levels, and prevented the progression of atherosclerosis in LDL receptor knockout mice. The results suggest that the reduction in plasma remnants through the action of lipoprotein lipase is an effective way to treat atherosclerotic disorders such as familial hypercholesterolemia. Finally, we have tried gene therapy, which will be an important therapeutic approach to correct genetic abnormalities found in metabolic diseases, for the prevention of atherosclerosis.

在转基因小鼠或基因敲除小鼠中，可以转导或删除特定基因以研究其功能及其与人类疾病的关系。最近，已经建立了过表达或缺乏特定基因的各种转基因小鼠或基因敲除小鼠系，可用于研究动脉粥样硬化、糖尿病和高脂血症等人类疾病的病理生理学。我们已经建立了整合了大鼠apoE基因和人脂蛋白脂酶基因的转基因小鼠品系。apoE的过表达降低血浆胆固醇和甘油三酯水平，并防止饮食诱导的高胆固醇血症。建立了另一种在动脉壁中过表达受H2 Ld启动子控制的apoE的转基因模型。在该模型中，脂肪条纹病变的形成被显著抑制，表明apoE具有抗动脉粥样硬化作用。为了建立新的动脉粥样硬化动物模型，将脂蛋白脂酶过表达转基因小鼠与LDL受体敲除小鼠杂交。脂蛋白脂酶的过度表达显著降低血浆残余水平，并阻止LDL受体敲除小鼠动脉粥样硬化的进展。结果表明，通过脂蛋白脂酶的作用减少血浆残留物是治疗动脉粥样硬化性疾病如家族性高胆固醇血症的有效方法。最后，我们尝试了基因治疗，这将是一个重要的治疗方法，以纠正在代谢疾病中发现的遗传异常，以预防动脉粥样硬化。