Development of transgenic rabbits as models for atherosclerotic research

为了研究动脉粥样硬化，我们于1998年底成功地培育了表达人载脂蛋白(A)[Lp(A)]或脂蛋白脂酶(LPL)的转基因兔。11只兔子被发现转基因整合到它们的基因组中。3只转基因兔出生后不久，5只转基因兔在血浆中未检测到apo(A)的表达。建立了3个转基因兔系，其中A01系血浆apo(A)含量为1.8 mg/dl，A46系为3.4 mg/dl，A47系为4.5 mg/dl。将A_(10)系选育成F_1和F_2，获得以下结果：人载脂蛋白(A)基因主要在肝脏和肾脏中表达。转基因兔的血浆载脂蛋白(A)在前β位置表现出与人Lp(A)相似的流动性。与转基因小鼠血浆不同，转基因兔血浆中约有80%的apo(A)与兔apo-B共价结合，并存在密度为1.02~1.10g/ml的级分，表明Lp(A)的形成。这些结果表明，表达人载脂蛋白(A)的转基因兔能够有效地组装Lp(A)，可作为研究人Lp(A)的动物模型。现在，我们已经开始通过饲喂高胆固醇饲料来培育更多的F1代来用于动脉粥样硬化的研究。转LPL基因兔：到目前为止，我们已经培育出3只鸡b-肌动蛋白启动子控制下的LPL转基因兔和4只清道夫受体启动子控制下的LPL转基因兔。对这些转基因兔子的鉴定目前正在进行中。

For the study of atheroslerosis, we have successfully generated transgenic rabbits expressing either human apolipoprotein(a) [Lp(a)] or lipoprotein lipase (LPL) at the end of 1998.Apo(a) transgenic rabbits :Totally, 93 pups were obtained after transplantation into foster mothers. 11 rabbits were found to have transgene integrated into their genome. 3 transgenic rabbits soon after birth and 5 transgenic rabbits show no detectable expression of apo(a) in the plasma. 3 transgenic rabbit lines have been established ; A01 line has 1.8mg/dl, A46 line has 3.4 mg/dI, and A47 line has 4.5 mg/dl of apo(a) in the plasma. A10 line has been bred into F1 and F2 and the following results were obtained. Human apo(a) mRNA expression was mainly found in the liver and kidney. Plasma apo(a), in transgenic rabbits showed a similar mobility to human Lp(a) at pre-beta position. In the plasma of transgenic rabbits, unlike the plasma of transgenic mice, about 80% of the apo(a) was covalently associated with rabbit apo-B and was contained in the fractions with density 1.02-1.10 g/ml, indicating the formation of Lp(a). These results suggest that transgenic rabbits expressing human apo(a) exhibit efficient assembly of Lp(a) and can be used as an animal model for the study of human Lp(a). Now, we have started to breed more F1 for the study of atherosclerosis by feeding cholesterol-rich diet.LPL transgenic rabbits :Until now, we have produced 3 LPL transgenic rabbits under the control of chicken b-actin promoter and 4 LPL transgenic rabbits under the control of scavenger receptor promoter. Characterization of these transgenic rabbits are currently underway.