CHOLINE DEFICIENCY AND HEPATOCARCINOGENESIS

本申请中提出的研究旨在进一步 描述了大鼠肝癌发生的营养模型， 无胆碱饮食 当喂食雄性大鼠时，饲料诱导肝细胞 死亡和再生，以及肝癌。另一方面，雌性大鼠 对饮食的肝致坏死作用有抵抗力， 患上肝癌 这种性别差异将被利用， 定义肝细胞死亡和再生在 探讨女性肝癌的发生机制 两者的抵抗。 在雄性大鼠中发展的肝癌携带 p53基因突变，并将进行研究以表征 突变，无论是单个还是多个，其位点，以及 涉及的核苷酸;并且，为了确定它是否发生在 治疗大鼠，因此可能是一个基因组改变有助于 在这个模型中， 致癌作用 除了本身是肝癌， 饮食是一种强致癌物。 其他研究将探讨 老鼠的性别是否也会影响这种行为， p53突变的发生或表达。 已知老鼠的肝脏含有 “自发”启动的细胞。 对这些细胞的兴趣正在增长，因为 它们可能参与化学诱导的癌的发生， 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 因此，建议探讨获得孤立和 这些细胞的纯化制剂用于直接研究。 人类的 男性肝癌发病率高于女性， 肝癌与慢性肝病之间存在联系 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.