CHOLINE DEFICIENCY AND HEPATOCARCINOGENESIS

本申请中提出的研究旨在进一步 大鼠肝细胞癌发生的营养模型 缺乏胆碱的饮食。当喂给雄性大鼠时，这种饮食会诱导肝细胞 死亡和再生，以及肝癌。另一方面，雌性老鼠 对饮食的促肝作用有抵抗力，而不是 患上肝癌。这种性别差异将被更好地利用 明确肝细胞死亡和再生在疾病中的作用 肝癌的发生，并探讨女性肝癌的发病机制 对两者都有抵触情绪。在雄性大鼠体内发生的肝癌携带 P53基因突变(S)，并将进行研究，以表征 突变(S)，无论是单个还是多个，其位点(S)，以及 参与的核苷酸；以及，确定它是否发生在早期(S) 对大鼠的治疗，因此可能是基因组的改变，有助于 大鼠肝细胞癌变的实验研究 致癌。除了本身会导致肝癌，一种缺乏胆碱的 饮食是一种很强的致癌物质。其他研究将解决 老鼠的性别是否也会影响这一行为，以及 P53突变的发生或表达。已知的老鼠肝脏中含有 “自发地”启动了细胞。人们对这些细胞的兴趣正在增长，因为 它们可能参与了化学物质诱发的癌症的发生，如 以及肝癌发生的非化学模型。目前， 然而，人们对这些细胞的性质知之甚少。我们是 因此，建议探索获得隔离和 用于直接研究的这些细胞的纯化制剂。在人类中， 男性的肝癌发病率高于女性，而且 肝细胞癌与慢性肝病的关系 损坏和修复。因此，拟议的研究也与 人类疾病实体的背景。

The studies proposed in this application are designed to further characterize the nutritional model of hepatocarcinogenesis in rats fed a choline-devoid diet. When fed to male rats, the diet induces liver cell death and regeneration, and liver cancer. on the other hand, female rats are resistant to the hepatonecrogenic action of the diet, and do not develop liver cancer. This sex difference will be exploited to better define the role played by liver cell death and regeneration in hepatocarcinogenesis, and to probe into the mechanisms of female's resistance to both. Liver cancer that develops in male rats carry mutation(s) of the p53 gene, and studies will be performed to characterize the mutation(s), whether single or multiple, its site(s), and the nucleotides involved; and, to determine whether it occur (s) early in the treatment of the rats, and may thus be a genomic alteration contributing to the neoplastic transformation of liver cells in this model of carcinogenesis. Beside being hepatocarcinogenic per se, a choline-devoid diet acts as a strong co-carcinogen. Other studies will address the question of whether the sex of the rats influences that action too, and the occurrence or expression of p53 mutations. Rat liver is known to contain "spontaneously" initiated cells. Interest in these cells is growing, since they could be involved in the genesis of carcinomas induced by chemical, as well as non-chemical models of hepatocarcinogenesis. At the present time, though, very little is known about the properties of these cells. We are therefore proposing to explore the feasibility of obtaining isolated and purified preparations of these cells for direct study. In humans, the incidence of liver carcinoma is higher in males than in females, and a high association exists between hapatic cancer and chronic conditions of liver damage and repair. The proposed studies are therefore relevant also in the context of the human disease entities.