Studies on mechanisms apoptosis and carcinogenesis of hepatocytes in hereditary liver disease and approaches for gene therapy for liver diseases

遗传性酪氨酸血症I型（HTI，富马酰乙酸水解酶缺乏症）的特点是严重的肝脏疾病和肝癌的高发。在本研究中，我们通过HT1的动物模型来阐明该疾病的癌变机制。此前，我们将缺陷的HPD基因导入白化病致死小鼠，先后挽救了表型。在本研究中，我们给药均质酸导致这些小鼠的肝脏凋亡。得到如下结果：(i)用caspase抑制剂抑制富马酰乙酸引起的肝细胞和肾小管上皮细胞凋亡。（ii）观察细胞周期时，富马酰乙酸损伤的细胞在G2M时被阻滞。（iii）表达人富马酰乙酸水解酶的重组腺病毒对小鼠肝损伤有保护作用。此外，表达人富马酰乙酸水解酶的重组腺相关病毒也能拯救小鼠。（iv）在模型小鼠中施用均质酸，以促进肿瘤的发生。在组织学检查中，肝脏出现异常细胞，但本研究未证实明显的癌。

Hereditary tyrosinemia type I (HTI, fumarylacetoacetate hydrolase deficiency) is characterized by severe liver disease and high incidence for liver carcinomas. In this study, we investigated animal model for HT1 to elucidate mechanisms for carcinogenesis in this disease. Previously, we introduced defective HPD gene into albino lethal mice and successively rescued the phenotype. In the present study, we administered homogentisic acid which lead to liver apoptosis in these mice.Following results are obtained.(i) Apoptosis induced by fumarylacetoacetate in hepatocytes and renal tubular epithelial cells were prevented by the administration of caspase inhibitors.(ii) When cell cycles were investigated, the cells injured by fumarylacetoacetate were arrested at G2M.(iii) Recombinant adenovirus expressing human fumarylacetoacetate hydrolase prevents the liver damage and rescue the mice. In addition, recombinant adeno associated virus expressing human fumarylacetoacetate hydrolase rescues the mice.(iv) Administration of homogentisic acid in the model mice was attempted for development of carcinoma. On histological examinatios, abnormal cells were appeared in the livers however, apparent carcinoma was not confirmed in the present study.