GLYCOLIPID CHANGES DURING CHEMICAL HEPATOCARCINOGENESIS

化学性肝癌发生过程中糖脂的变化

• 批准号: 3460248
• 负责人: GARY K OSTRANDER
• 金额: $ 8.62万
• 依托单位: OKLAHOMA STATE UNIVERSITY STILLWATER
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-09-01 至 1995-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3460248
• 关键词: carbohydrate structure; chemical carcinogen; chemical carcinogenesis; chemical related neoplasm /cancer; dosage; embryo /fetus cell /tissue; glycolipids; glycosphingolipids; histopathology; lipid biosynthesis; liver neoplasms; liver regeneration; nitrosoguanidines; preneoplastic state; tissue /cell culture; trout /salmon

Glycosphingolipids (glycolipids) are membrane bound cell surface antigens occurring in nearly all vertebrate tissues. Structural modifications of the carbohydrate moiety were originally observed in association with end- stage tumorigenesis. Subsequently, these changes were shown to appear during a premalignant stage of chemical carcinogenesis. Thus, glycolipid alterations may be of functional significance during chemical carcinogenesis. Proposed herein are studies to enhance understanding of the nature of glycolipid alterations during chemical hepatocarcinogenesis. A departure from traditional carcinogenesis studies entails utilization of rainbow trout. Studies with trout will permit exploitation of novel aspects of this model system. First generations experiments include whole animal tumor induction studies with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) to elucidate specific glycolipid changes throughout carcinogenesis. These experiments will utilize high doses of carcinogen to insure adequate tumor tissue for characterizing glycolipid alterations. Second generation experiments will follow traditional complete carcinogenesis as well as initiation/promotion regiments with MNNG. Sensitive probes developed from the first generation experiments will be used to elucidate the ontogeny of these alterations. Coincident with these experiments will be detailed study of the histology of developing lesions (preneoplastic foci through end-stage tumors). Thus, it will be possible ascertain the specificity of particular lesion types with altered glycolipid profiles. Glycolipids will be isolated and examined from normal and premalignant tissues, tumors, and cell lines as well as fetal, developing, and regenerating liver. From such comparisons the nature and extent of glycolipid alterations will be determined. The enzymatic lesion(s) associated with these alterations will then be investigated to ascertain the manner in which such modifications in carbohydrate structure are mediated. Finally, information collected concerning glycolipid changes during chemical carcinogenesis in the rainbow trout will be carefully compared and contrasted with published mammalian studies to provide a broader base for further understanding of the significant role of glycolipids during carcinogenesis in all vertebrate species.

鞘糖脂是一种膜结合的细胞表面抗原 几乎存在于所有脊椎动物组织中。结构上的修改 碳水化合物的部分最初被观察到与末端- 处于肿瘤发生的阶段。随后，这些变化被显示出来 在化学致癌的癌前阶段。因此，糖脂 在化学过程中，变化可能具有重要的功能意义 致癌。 在此建议进行研究，以加强对 化学性肝癌发生过程中糖脂的变化。一次离开 来自传统的致癌研究需要利用彩虹 鲑鱼。对鲑鱼的研究将允许开发新的方面 这个模型系统。第一代实验包括整个动物 N-甲基-N‘-硝基-N-亚硝胺(MNNG)对小鼠肿瘤的诱导作用 阐明特定糖脂在癌变过程中的变化。这些 实验将利用高剂量的致癌物质来确保足够的肿瘤 用于表征糖脂变化的组织。第二代 实验将遵循传统的完全致癌方法以及 MNNG的启蒙/提拔团。敏感的探头是从 第一代实验将被用来阐明 这些变化。与这些实验相吻合的内容将会详细介绍 进展性病变(癌前病变、癌前病变)的组织学研究 终末期肿瘤)。因此，将有可能确定 糖脂分布改变的特殊病变类型。糖脂将 从正常和癌前组织、肿瘤和 细胞系以及胎儿、发育和再生的肝脏。从这样的 比较糖脂改变的性质和程度将是 下定决心。与这些改变相关的酶损伤(S)将 然后进行调查，以确定此类修改在 碳水化合物的结构是被调节的。 最后，收集到的有关糖脂变化的信息 我们将仔细比较虹鱼体内的化学致癌作用 与已发表的哺乳动物研究形成对比，为 进一步认识糖脂在人体内的重要作用 在所有脊椎动物中都有致癌作用。