低密度脂蛋白受体敲除仓鼠：一个新型代谢性心血管疾病模型的建立

Hamster is different in lipid metabolism with mouse and rat, such as cholesteryl ester transfer protein (CETP) highly expressed, liver without apolipoprotein B48 editing activity. These features are highly similar to human being. Therefore, hamster has the same plasma lipoprotein profile and response to high-fat diet with humans. Hamster is an excellent animal model for human cardiovascular disease. However, because of technical problems, our group was the first to develop genetic engineering hamster model successfully until last year. Then we prepared subsequently the LDL receptor knockout (LDLR KO) hamsters. The homozygous and heterozygous plasma cholesterol increased 4 times and 50% without high fat high cholesterol diets, so that the phenotype of the model is consistent with human familial hypercholesterolemia. This project aims to take this as a basis to establish the man-like atherosclerosis (As) small animal models. We will systematically compare three LDLR KO models of mice, rats and hamsters to confirm the phenotypic characteristics and advantages of hamsters. And we will establish a small animal model of coronary heart disease by the introduction of environmental factors. We will also make it clear LDLR KO hamsters have the value of application in anti-As new drug development. The implementation of this project will establish man-like cardiovascular disease small animal models to provide a new platform of animal model for the studies not suitable using rats and mice. And it will creat and lead a new study field of man-like cardiovascular disease small animal models.

仓鼠在脂代谢方面与大小鼠不同，胆固醇酯转运蛋白（CETP）高表达，肝脏没有载脂蛋白B48编辑活性，而与人类高度相似。因此血浆脂蛋白谱、对高脂饲料的反应也均与人类相同，是人类心血管疾病的极佳动物模型。然而因为技术难题，基因工程仓鼠直到去年才由本研究组率先研发成功。目前我们又制备了低密度脂蛋白受体敲除（LDLR KO）仓鼠，杂合子及纯合子的血浆胆固醇不需要喂饲高脂饲料就增高50%和4倍，与人类家族性高胆固醇血症相似。本项目拟以此为基础，建立类人化动脉粥样硬化（As）小动物模型。我们将系统地比较大、小鼠和仓鼠三种动物的LDLR KO模型，确认仓鼠的表型特点和优势，引入环境因素建立冠心病小动物模型，并明确LDLR KO仓鼠在抗As新药研发上的应用价值。本项目的实施将建立类人化小型心血管疾病动物模型，为不适合使用大小鼠的研究提供新的模式动物平台，开创和引领一个类人化的小型心血管疾病动物模型新领域。

本项目在我们在国际上首次建立新型的类人化啮齿类动物——仓鼠的基因修饰技术平台基础上，为了弥补小鼠、大鼠和人类的脂代谢、糖代谢、动脉粥样硬化病理特点和人类差距甚远的缺陷，利用我们自己制备成功的低密度脂蛋白受体（LDLR）敲除仓鼠，以建立新型心血管疾病动物模型平台为目的，开展了有关心血管疾病的模型的研究。包括该动物模型的表型分析，仓鼠的动脉粥样硬化病理特点分析以及和人类相似性的分析，并且根据其特点建立了适合仓鼠的病变分析评估标准。项目还开展了冠脉动脉粥样硬化的诱导方法的建立，以及冠心病模型的制备方法的探讨，并通过仓鼠脂代谢特点的分析来理解仓鼠脂代谢和小鼠不同而和人类相似的病生理机制，并且通过此理解冠心病的发病机制和代谢的关系。另外，我们将此动物模型平台扩展到中风、脂肪肝、急性胰腺炎等和脂代谢密切相关的疾病模型的研究。本项目的结果不仅显示仓鼠是一个使用便利经济的类人化的模式动物，而且LDLR敲除仓鼠模型能够广泛应用到心血管疾病的研究中，应用到降脂、心脏保护等药物的研发，也同时为冠心病研究缺乏合适的动物模型的困境找到了突破口。