Rubin E M, Lu R H, Cooper S, Mohandas N, Kan Y W
Howard Hughes Medical Institute, University of California, San Francisco.
Am J Hum Genet. 1988 Apr;42(4):585-91.
Owing to the episodic and unpredictable nature of the sickling crisis, many aspects of the disease sickle cell anemia have resisted in vivo analysis. The lack of an animal model has hindered the pathophysiological investigation of this disease, as well as deterred the development of pharmacological therapies. The transgenic mouse system offers a new means for creating animals that make a specified mutant gene product, and we have used this system to create a series of mice that contain the human beta s-globin gene. These animals express this gene in the appropriate tissues and at the same point in development as the adult mouse globin genes are expressed. We have crossed the human beta s-containing transgenic mice with a beta-thalassemic mouse line and examined the hemoglobins produced by these mice. Their red cells contain 10% mouse alpha/human beta s hybrid hemoglobin, which partially corrects the thalassemic phenotype of the homozygous beta-thalassemic animals. Though the red cells do not sickle, other properties of the human beta s gene in these mice indicate the potential for the eventual development of a transgenic animal model for sickle cell anemia.
由于镰状细胞危象具有发作性和不可预测性，镰状细胞贫血这种疾病的许多方面一直难以进行体内分析。缺乏动物模型阻碍了对该疾病的病理生理学研究，也阻碍了药物治疗的开发。转基因小鼠系统为创造能产生特定突变基因产物的动物提供了一种新方法，我们已利用该系统培育出一系列携带人类βs-珠蛋白基因的小鼠。这些动物在适当的组织中表达该基因，且在发育过程中的表达时间与成年小鼠珠蛋白基因的表达时间相同。我们已将携带人类βs基因的转基因小鼠与β地中海贫血小鼠品系进行杂交，并检测了这些小鼠产生的血红蛋白。它们的红细胞含有10%的小鼠α/人类βs杂合血红蛋白，这部分纠正了纯合β地中海贫血动物的地中海贫血表型。尽管这些小鼠的红细胞不会发生镰变，但人类βs基因在这些小鼠中的其他特性表明，最终有可能开发出镰状细胞贫血的转基因动物模型。
