ALCOHOL INTAKE AND RETINOID METABOLISM AND SIGNALING

酒精摄入量和视黄醇代谢及信号转导

• 批准号: 6473182
• 负责人: XIANG-DONG WANG
• 金额: $ 28万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6473182
• 关键词: JUN kinase; alcoholism /alcohol abuse; all trans retinol; behavioral /social science research tag; biological signal transduction; cell proliferation; chemical carcinogenesis; ethanol; hepatocellular carcinoma; laboratory rat; neoplasm /cancer nutrition therapy; nonhuman therapy evaluation; nutrition related tag; retinoids; vitamin metabolism

DESCRIPTION (provided by applicant): Our long-term objective is to study the +___________________________________ chemopreventive effect of retinoids on chronic and excessive alcohol related carcinogenesis in the liver and peripheral organs. The present grant proposal focuses on cell proliferation, which plays a central role in hepatic carcinogenesis in both the initiation and promotion stages, particularly when chemical carcinogens are involved. Retinoic acid plays an important role in controlling carcinogenic progression in a variety of cancers, including liver cancer. One of the chemopreventive effects of retinoids is thought to be mediated through control of proliferation via delaying progression of damaged cells into S phase, which allows for DNA repair and induction of apoptosis, thereby reducing the risk of carcinogenic initiation. However, long term and excessive ethanol intake reduces hepatic retinoid levels. The observation that retinoid concentrations are decreased in both plasma and cancerous liver tissues of hepatocarcinoma patients, suggests a role for retinoid depletion in hepatocarcinogenesis. However, it is not known 1) whether chronic ethanol-induced hepatocellular proliferation (which could convert hepatocytes from a state of resistance to a carcinogen to a state of susceptibility) is due to alcohol-impaired retinoid metabolism and signaling, and if so, 2) whether restoration of retinoid status by either inhibiting ethanol-induced retinoid catabolism or supplementing retinoic acid can suppress both ethanol-induced cell hyperproliferation as well as ethanol-promoted (diethylnitrosamine induced) hepatocellular carcinogenesis. We will investigate the possible role of diminished retinoid signaling and/or the up-regulation of the Jun N-terminal kinases-dependent (JNK) signaling pathway by chronic ethanol treatment on alcohol induced hepatocellular cell proliferation as well as alcohol-promoted hepatocellular carcinogenesis (induced by diethylnitrosamine). Simultaneously, we will test whether treatment with either chlormethiazole (an inhibitor of retinoic acid catabolism) and all-trans retinoic acid in ethanol-fed rats can inhibit alcohol-induced hepatocellular cell proliferation as well as alcohol-promoted hepatocellular carcinogenesis via either restoring normal retinoid signaling and/or inhibiting the JNK dependent signaling pathway. This study will be the first to link the regulation of retinoid signaling with Jun N-terminal kinases-dependent pathway, cell proliferation and apoptosis in an alcohol-treated, chemically induced carcinogenesis animal model, which would have implications for the prevention and treatment of alcohol related human cancers.

描述（由申请人提供）：我们的长期目标是研究 +___________________________________ 维甲酸对慢性酒精中毒的化学预防作用 肝脏和周围器官的致癌作用。目前的赠款建议 重点关注细胞增殖，其在肝脏中起着核心作用。 在启动和促进阶段的致癌作用，特别是当 涉及化学致癌物。视黄酸起着重要作用， 控制各种癌症的致癌进展，包括肝癌 癌维甲酸的化学预防作用之一被认为是 通过延迟受损细胞的进展来控制增殖 细胞进入S期，这允许DNA修复和诱导凋亡， 从而降低致癌起始的风险。但是，长期和 过量的乙醇摄入会降低肝脏类维生素A水平。的观察结果 血浆和肝癌中的类维生素A浓度均降低 肝癌患者的组织中，表明类维生素A耗竭的作用， 肝癌发生然而，尚不清楚1）是否慢性 乙醇诱导的肝细胞增殖（其可将肝细胞转化为 从对致癌物的抵抗状态到易感状态）是由于 酒精损伤类维生素A代谢和信号，如果是这样，2）是否 通过抑制乙醇诱导的类维生素A 维生素A或补充维甲酸可抑制乙醇诱导的 细胞过度增殖以及乙醇促进的（二乙基亚硝胺 诱导）肝细胞癌发生。 我们将研究类维生素A信号减弱和/或 Jun N-末端激酶依赖性（JNK）信号通路的上调 慢性乙醇处理对乙醇诱导的肝细胞凋亡的影响 增殖以及酒精促进的肝细胞癌发生 （由二乙基亚硝胺诱导）。同时，我们将测试治疗是否 与氯甲噻唑（视黄酸催化剂的抑制剂）和 全反式维甲酸可抑制酒精诱导的大鼠肝细胞凋亡 肝细胞增殖以及酒精促进肝细胞 通过恢复正常的类维生素A信号传导和/或抑制 JNK依赖性信号通路。 这项研究将是第一个将类维生素A信号的调节与 Jun N端激酶依赖性通路与细胞增殖和凋亡 酒精处理的化学诱导的致癌动物模型， 对预防和治疗与酒精有关的人类疾病具有重要意义。 癌的