ALCOHOL TRIGGERS DEVELOPMENT OF MALLORY BODIES IN DRUG PRIMED LIVERS

广泛的长期目标是确定Mallory小体形成的致病机制。其具体目的是：1)在药物诱导的MB形成模型中，确定药物再喂养、乙醇喂养和冈田酸处理过程中细胞角蛋白的构象变化。2)确定药物再喂养、酒精喂养和冈田酸处理过程中细胞角蛋白细丝的过度磷酸化是否参与药物诱导的小鼠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的形成中起作用，以防止错误折叠的细胞角蛋白蛋白的重折叠。4)确定泛素途径在细胞角蛋白的蛋白酶体蛋白分解中的作用。该方法将研究药物诱导的Mallory小体形成的小鼠模型，以确定假设与所谓的能够形成MBS的“空细胞”有关的事件序列。由于MB的形成是包括酒精性肝病在内的许多类型的肝脏疾病中肝细胞损伤的常见和重要的机制，对MB形成机制的新认识将使设计预防和治疗发现MB的肝病的治疗策略成为可能。总之，这项研究将增加对细胞质内角蛋白蛋白质合成、折叠、聚合、解聚和降解动力学的重要新理解，并解释当磷酸化和去磷酸化调节之间的平衡向过度磷酸化倾斜时，细胞角蛋白聚集体是如何在细胞内积累的，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.