Establishment Of The Mutant Human ApoAⅠ/CⅢ/AⅣ/AⅤ Gene Cluster Transgenic Mouse Mediated By BAC And Comparative Studies With The Intact ApoAⅠ Cluster Transgenic Mice

The human apolipoprotein family consists of 19 members and they mainly locate on five different chromosomes. The genes coding for apoAI, apoCIII, apoAIV, and apoAV are clustered within a 50 kb DNA fragment on the long arm of human chromosome 11. The transcriptional direction of apoCIII is opposite to the other genes in the cluster. The apo genes in the ApoAI gene cluster present tissue-specific expression: apoAI is expressed with high level in the liver and intestine, apoCIII synthesis occurs predominantly in the liver and to a much lesser extent in the intestine, and apoAIV is expressed mainly in the intestine and to a less extent in the liver, while apoAV is expressed only in the liver. The apoCIII gene enhancer, as a common regulatory element, directs the hepatic and intestinal expression of apoAI, apoCIII and apoAV. All apo genes in this cluster are closely linked to plasma lipid profiles and are associated with atherosclerosis: apoAI and apoAIV take part in the reverse cholesterol transport and are associated with the development of atherosclerosis; apoCIII and ApoAV have predominant while opposite roles in triglyceride homeostasis and concern hypertriglyceridemia and atherosclerosis. It is interesting to study the transcriptional regulation of ApoAI gene cluster and the roles of apo genes in combination in the lipid homeostasis and associated coronary heart diseases, especially atherosclerosis.Studies of transcriptional regulation of eukaryotic genes in transgenic mice permit not only the devices of experiments on molecular level but also the observation of the involvement of almost all the factors affecting gene regulations in vivo. Transgenic technique can be applied to set up transgenic models for human genetic diseases from which statement regulation of abnormal genes are demonstrated and many pre-clinical data for human gene therapy will be provided. As a new developing vector system, bacterial artificial chromosome (BAC) has several advantages: the average insert of BAC vector is...