Regulation of G0-G1 Transition in Hepatocytes

描述（由申请方提供）：在肝再生期间，静止肝细胞重新进入细胞周期，增殖并重新填充患病肝脏。这一过程在许多形式的急性肝损伤中观察到，特别是那些由病毒，毒素和创伤引起的急性肝损伤。因此，急性肝功能衰竭的预后通常取决于增殖超过肝细胞坏死的能力。这里概述的研究的长期目标是利用最近的知识，调节退出静止的事件，以确定肝再生启动的肝脏特异性靶点。本研究的第一个目的是评估新的细胞周期蛋白依赖性激酶活性，调节从静止到活跃的细胞周期的过渡。我们认为，细胞周期蛋白依赖性激酶的活动之前，典型的G1期细胞周期蛋白是重要的G0过渡到G1在再生过程中。该研究的第二个目的是设计一种基于siRNA的筛选，其靶向在肝再生的启动阶段上调的基因。目标是确定其产物是周期进展所必需的基因。我们的希望是确定生理相关的分子，可以作为治疗靶点，以增强肝脏增殖。使用H35大鼠肝细胞系的基于细胞的试验将用于两个研究系列，H35大鼠肝细胞系可以经历从静止到细胞周期再入的转变。

DESCRIPTION (provided by applicant): During liver regeneration, quiescent hepatocytes reenter the cell cycle, proliferate and repopulate the diseased liver. This process is observed in many forms of acute liver injury specifically those caused by viruses, toxins and trauma. Therefore, prognosis in acute liver failure often depends on the ability of proliferation to outlast liver cell necrosis. The long-term objective of the studies outlined here is to use recent knowledge of events that regulate exit from quiescence to identify liver specific targets in the initiation of liver regeneration. The first aim of the study is to evaluate for novel cyclin dependent kinase activities that regulate the transition from quiescence to active cell cycling. We believe that cyclin dependent kinase activities that precede the canonical G1 cyclins are important in transiting from G0 to G1 during the regenerative process. The second aim of the study is to design a siRNA based screen that targets genes up regulated in the priming phase of liver regeneration. The goal is to identify genes whose products are necessary for cycle progression. Our hope is to identify physiologically relevant molecules that can be therapeutic targets for enhancement of liver proliferation. A cell based assay using H35 rat liver cell line, which can undergo the transition from quiescence to cell cycle reentry, will be used for both lines of inquiry.