GLYCOLIPID CHANGES DURING CHEMICAL HEPATOCARCINOGENESIS

化学性肝癌发生过程中糖脂的变化

• 批准号: 3460247
• 负责人: GARY K OSTRANDER
• 金额: $ 8.29万
• 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/3460247
• 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（糖脂）是膜结合的细胞表面抗原 几乎发生在所有脊椎动物组织中。 结构修改 最初观察到碳水化合物部分与末端相关 肿瘤发生阶段。 随后，这些变化被证明出现了 在化学致癌作用的癌前阶段。 因此，糖脂 化学过程中的改变可能具有功能意义 致癌作用。 本文提出的研究旨在增强对本质的理解 化学性肝癌发生过程中糖脂的变化。 一次出发 传统的致癌研究需要利用彩虹 鳟鱼。 对鳟鱼的研究将允许开发鳟鱼的新颖方面 这个模型系统。 第一代实验包括整个动物 N-甲基-N'-硝基-N-亚硝基胍 (MNNG) 的肿瘤诱导研究 阐明整个致癌过程中特定糖脂的变化。 这些 实验将利用高剂量的致癌物来确保足够的肿瘤 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作用以及 与 MNNG 一起启动/晋升团。 敏感探头开发自 第一代实验将用于阐明个体发育 这些改变。 恰逢这些实验将详细 研究病变发展的组织学（癌前病灶至 终末期肿瘤）。 因此，可以确定 糖脂谱改变的特定病变类型。 糖脂会 从正常组织和癌前组织、肿瘤中分离并检查 细胞系以及胎儿、发育和再生肝脏。 从这样的 比较糖脂改变的性质和程度 决定。 与这些改变相关的酶损伤将 然后进行调查以确定此类修改的方式 碳水化合物结构是介导的。 最后，收集有关糖脂变化的信息 将仔细比较虹鳟鱼的化学致癌作用 与已发表的哺乳动物研究相比，为 进一步了解糖脂在过程中的重要作用 所有脊椎动物的致癌作用。