ALCOHOL TRIGGERS DEVELOPMENT OF MALLORY BODIES IN DRUG PRIMED LIVERS

广泛的长期目标是确定参与马洛里体形成的致病机制。具体目的是1）确定药物再补料期间细胞角蛋白的构象变化，[在MB形成的药物引发模型中，MB形成期间乙醇补料和冈田酸处理]。2)确定药物再喂养、酒精喂养和冈田酸处理期间细胞角蛋白丝的过度磷酸化是否参与药物致敏小鼠模型中的MB形成。3)确定热休克蛋白[伴侣蛋白重折叠]是否在防止MB形成中发挥作用，从而导致错误折叠的细胞角蛋白重折叠。4)确定MB形成过程中细胞角蛋白的蛋白酶体蛋白水解的泛素途径的作用。该方法将研究马洛里体形成的药物致敏小鼠模型，以确定假定参与已知能够形成MB的所谓“空细胞”的事件序列。由于MB形成是许多类型的肝病（包括酒精性肝病）中肝细胞损伤的常见且重要的机制，因此对MB形成机制的新认识应使设计治疗策略以预防和治疗发现MB的肝病成为可能。这项研究将增加对细胞角蛋白合成、折叠、聚合、这些结果解释了细胞角蛋白的解聚和降解，并解释了当磷酸化和去磷酸化调节之间的平衡向过度磷酸化的方向倾斜时，细胞角蛋白聚集体如何在细胞中积累，即MB形成。

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.