Transgenic mouse technology can be utilized to produce animals expressing a foreign gene to high levels of its RNA and protein. The objective of this project is to generate mice that contain an abnormal betaglobin gene (beta-sickle Antilles). This gene has two mutations and generates sickle cell anemia in a heterozygous individual. High level expression of the gene is obtained by inserting the dominant control region from the human beta globin locus in cis to the Antilles gene. This dominant control region allows high level globin expression to occur. The human alpha- globin gene is also inserted in cis in order to generate mice that can produce high levels of beta sickle Antilles and human alpha globins. Three independent transgenic mouse lines that express both human globin genes in a coordinated fashion have been generated. The production levels of the human globin chains in the founder mice is 15-20% compared to the mouse globin levels. The founder mice exhibit sickling erythrocytes in vitro but not in vivo. To generate in vivo sickling, the levels of human globins will be increased by breeding the animals to homozygosity and by mating them with thalassemic mice.
