ALCOHOL TRIGGERS DEVELOPMENT OF MALLORY BODIES IN DRUG PRIMED LIVERS

酒精触发药物启动肝脏中马洛里体的发育

• 批准号: 6618849
• 负责人: SAMUEL William FRENCH
• 金额: $ 17.85万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6618849
• 关键词: alcoholic liver cirrhosis; conformation; cytoplasm; drug metabolism; ethanol; gene expression; inclusion body; infrared spectrometry; intermediate filaments; keratin; laboratory mouse; liver cells; liver disorder; northern blottings; okadaic acid; posttranslational modifications; protein binding; protein folding; protein metabolism; proteolysis; stress proteins; toxicology; ubiquitin; western blottings

Broad long term objectives are to determine the pathogenic mechanisms involved in Mallory body formation. The specific aims are to 1) To determine the conformational changes in the cytokeratins during drug refeeding, [ethanol feeding and okadaic acid treatment during MB formation in the drug primed model of MB formation.] 2) To determine if hyperphosphorylation of cytokeratin filaments during drug refeeding, alcohol feeding and okadaic acid treatment is involved in MB formation in the drug primed mouse model. 3) To determine if heat shock protein [chaperone protein refolding] plays a role in preventing MB formation causing refolding of misfolded cytokeratin proteins. 4) To determine the role of the ubiquitin pathway of proteasome proteolysis of cytokeratins during MB formation. The approach will be to study the drug primed mouse model of Mallory body formation to determine the sequence of events postulated to be involved in the so called "empty cells" which are known to be capable of forming MBs. Since MB formation is a common and importan6t mechanism of liver cell injury in many types of liver disease including alcoholic liver disease, this new insight into the mechanisms involved in MB formation should make it possible to design treatment strategies to prevent and treat liver diseases where MBs are found. In summary: The study proposed will add important new understanding of the intracytoplasmic dynamics of cytokeratin protein synthesis, folding, polymerization, depolymerization and degradation as well as explain how cytokeratin aggregates accumulate in the cell, i.e. MB formation, when the balance between phosphorylation and dephosphorylation regulation is tipped in the direction of hyperphosphorylation.

广泛的长期目标是确定马洛里体形成中涉及的致病机制。具体目标是 1) 确定药物再喂养期间细胞角蛋白的构象变化，[在药物引发的 MB 形成模型中，在 MB 形成过程中进行乙醇喂养和大田酸处理。] 2) 确定药物期间细胞角蛋白丝是否过度磷酸化在药物引发的小鼠模型中，重新喂养、酒精喂养和冈田酸治疗参与了MB的形成。 3) 确定热休克蛋白[伴侣蛋白重折叠]是否在防止MB形成导致错误折叠的细胞角蛋白重折叠方面发挥作用。 4)确定细胞角蛋白蛋白酶体蛋白水解的泛素途径在MB形成过程中的作用。该方法将研究马洛里体形成的药物引发小鼠模型，以确定假定涉及所谓“空细胞”的事件序列，这些“空细胞”已知能够形成MB。由于MB形成是包括酒精性肝病在内的许多类型肝病中肝细胞损伤的常见且重要的机制，因此对MB形成机制的新见解应该使得设计治疗策略来预防和治疗MB的肝病成为可能。被发现。总之：该研究将为细胞角蛋白合成、折叠、聚合、解聚和降解的细胞质内动力学增加重要的新认识，并解释当磷酸化和去磷酸化之间的平衡达到平衡时，细胞角蛋白聚集体如何在细胞中积累，即MB形成。调节朝着过度磷酸化的方向倾斜。