α-1 抗胰蛋白酶缺乏症是一种常染色体共显性遗传性肝脏疾病，以血液中低水平的α-1 抗胰蛋白酶为特征，主要表现为新生儿与成年人的肺肝损伤，肺肝移植是终末期治疗的选择。由于供体器官的严重缺乏，肝细胞移植是一种潜在的治疗方法。我们研究发现野生株小鼠肝细胞移植到α-1 抗胰蛋白酶缺乏症转基因小鼠肝脏中经过180天后自发性地代替了98%宿主肝细胞，给小鼠注射表达肝细胞生长因子的腺病毒明显加速移植肝细胞的生长。供体肝细胞可以同时替代含有或不含有突变蛋白球状体的宿主肝细胞，这些结果提示肝细胞移植可用来治疗α-1 抗胰蛋白酶缺乏症。本项目将在此基础上，使用基因转染技术建立α-1 抗胰蛋白酶缺乏症小鼠模型，通过脾髓等途径移植不同来源的人肝细胞到小鼠肝脏。重点研究移植的人肝细胞在异体肝脏中定植与增生的机制和对提高血液中人α-1 抗胰蛋白酶水平的贡献，来证明人肝细胞移植可用来治疗α-1 抗胰蛋白酶缺乏症。

α-1 Antitrypsin deficiency (AATD) is an autosomal dominant hereditary liver disease characterized by low level of AAT in blood , which is mainly manifested in neonatal and adult’s lung & liver injury. Lung and/or liver transplantation is the choice of the end stage treatment. Because of the serious shortage of the donor organs, hepatocyte transplantation may be potential therapeutic for AATD. We have already found out that Wild-type donor hepatocytes spontaneously replaced 98% of mutant host hepatocytes 180 days after transplantation，and repopulation was accelerated by injection of an adenovector expressing hepatocyte growth factor. Donor cells replaced both globule-devoid and globule-containing cells which accumulate mutant protein. These results suggest that wild-type hepatocyte transplantation may be therapeutic for α-1 Antitrypsin deficiency. Based on above results, a mouse model of α-1 Antitrypsin deficiency will be established using mutant gene transfection method and human hepatocytes from different origin or sources were delivered to the liver by injection into the splenic pulp or others. We will focus on the mechanism of human hepatocyte engraftment and proliferation in allogeneic liver and the donor cell’s contribution for blood human α-1 antitrypsin level to prove that human hepatocyte transplantation is high potential therapeutic for α-1 Antitrypsin deficiency disease.