CELL PROLIFERATION & LIVER CARCINOGENESIS

细胞增殖

• 批准号: 3189475
• 负责人: DITTAKAVI S SARMA
• 金额: $ 5.58万
• 依托单位: UNIVERSITY OF TORONTO
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-03-01 至 1991-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3189475
• 关键词: acetates; acyl coA; alkenes; cell growth regulation; cellular oncology; chemical carcinogen; chemical carcinogenesis; hepatectomy; liver cells; liver neoplasms; mitogens; molecular oncology; nitrates; orotate; phenobarbital; tumor promoters

The present proposal reflects our ongoing efforts to understand the initiation phase of the carcinogenic process at molecular level. The rationale for the investigation stems from our recent observation that mitogen-induced liver cell proliferative stimulus, unlike compensatory liver cell proliferative stimulus did not achieve initiation phase of the liver carcinogenic process. This observation was very significant because even though both types of stimuli induce liver cell proliferation one (compensatory type) achieves initiation while the other (mitogen-induced) does not. In our opinion an in depth analysis of this intriguing phenomenon may reveal the molecular mechanisms by which compensatory cell proliferation achieves initiation process. In initial experiments rats will be given non-necrogenic doses of carcinogens at the peak of liver DNA synthesis induced by liver mitogens and PH or CC14. The initiated hepatocytes will be promoted to grow and form foci of enzyme altered hepatocytes, hepatic nodules and hepatocellular carcinoma. To establish the generality of the phenomenon, three different initiators; four different liver mitogens such as lead nitrate, cyproterone acetate, nafenopin and ethylene dibromide and two different promoters such as orotic acid and phenobarbital will be used. In the next series, experiments will be designed to test the hypothesis that mitogen-induced liver cell proliferation, like compensatory liver cell proliferation achieves initiation but the initiated hepatocytes are selectively lost by apoptosis during the regression phase that accompanies mitogen-induced liver cell proliferation. Since this study approaches differently into the role of cell proliferation in initiation phase we may be in for several pleasant surprises. In addition, if initiated hepatocytes are uniquely susceptible to apoptosis, can this be an efficient means of eliminating the initiated hepatocytes.

目前的建议反映了我们正在努力了解 分子水平上致癌过程的起始阶段。 调查的理由源于我们最近的 观察到有丝分裂原诱导的肝细胞增殖刺激， 与代偿性肝细胞增殖刺激不同， 达到肝脏致癌过程的起始阶段。 这 观察结果非常重要，因为尽管这两种类型的 刺激诱导肝细胞增殖1（代偿型） 实现启动，而另一个（促分裂原诱导的）不。 在我们看来，深入分析这一有趣的现象， 可能揭示了代偿细胞 增殖达到起始过程。 在最初的实验中，大鼠将被给予非坏死剂量的 在肝脏诱导的肝DNA合成高峰期的致癌物 有丝分裂原和PH或CC 14。 启动的肝细胞将 促进生长并形成酶改变的肝细胞灶， 肝结节和肝癌。 建立 现象的一般性，三个不同的发起人;四个 不同的肝有丝分裂原如硝酸铅，醋酸环丙孕酮， 萘诺平和二溴化乙烯以及两种不同的促进剂， 因为将使用乳清酸和苯巴比妥。 在下一个系列中，将设计实验来测试 假设有丝分裂原诱导的肝细胞增殖，如 代偿性肝细胞增殖开始，但 启动的肝细胞在细胞凋亡过程中选择性地丢失， 伴随有丝分裂原诱导的肝细胞退化期 增殖 由于这项研究对细胞作用的研究方法不同， 在初始阶段的增殖，我们可能会在几个愉快的 惊喜 此外，如果启动的肝细胞是唯一的 易受细胞凋亡的影响，这是否是一种有效的手段， 清除启动的肝细胞。