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)确定药物引发MB形成模型中细胞角蛋白在再喂药、乙醇喂药和冈田酸处理期间MB形成过程中的构象变化。2)在药物诱导小鼠模型中，确定再喂药、酒精喂药和冈田酸处理过程中细胞角蛋白丝的过度磷酸化是否参与MB的形成。3)确定热休克蛋白[伴侣蛋白重折叠]是否在阻止MB形成导致错误折叠的细胞角蛋白重折叠中起作用。4)确定泛素途径在MB形成过程中蛋白酶体蛋白水解细胞角蛋白的作用。该方法将研究马洛里体形成的药物启动小鼠模型，以确定所谓的“空细胞”（已知能够形成MBs）所涉及的事件顺序。由于MB的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一个常见且重要的机制，因此对MB形成机制的新认识应该使设计治疗策略成为可能，以预防和治疗发现MB的肝脏疾病。综上所述，该研究将为细胞角蛋白合成、折叠、聚合、解聚和降解的胞质内动力学提供重要的新认识，并解释当磷酸化和去磷酸化调节之间的平衡向超磷酸化方向倾斜时，细胞角蛋白聚集体如何在细胞内积累，即MB的形成。

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.