MRP 2 (CMOAT) EXPRESSION IN HEPATOCELLULAR PROLIFERATION

已知肝细胞在应答中进行主动复制， 在有丝分裂刺激或化学后再生期间， 毒性对肝毒性剂的作用具有抗性。但 这种弹性的机制仍然是未知的。我们的试点研究 实验室证明， 给药亚致死剂量的两种模型肝毒物（对乙酰氨基酚 和四氯化碳）的小管表达增加 有机阴离子的ATP依赖性外排泵，称为MRP-2，或者 称为小管MRP（cMRP）或c MOAT。我们假设， 肝细胞增殖导致这种表达增加， 蛋白本提案中各项研究的总体目标是更好地 表征这种转运蛋白的上调， 有助于增殖的肝细胞对化学， 诱导损伤。我们的第一个目标是检查MRP-2中的时间变化 表达及其在肝细胞再生过程中的组织分布。然后 我们将确定是否使用 类似地，补偿性增生和直接有丝分裂的其它模型 增强MRP-2的表达。在这个领域补助金概述的研究应该 为将来的研究提供基础，旨在阐明功能性 这种蛋白质在增殖细胞中表达变化的后果， 肝细胞我们想提出这样一个概念，即上调 MRP-2可能是肝细胞增殖的几种机制之一， 获得对化学伤害的抵抗力。

It is known that hepatocytes undergoing active replication in response to mitogenic stimulation or during regeneration following chemical toxicity are resistant to the actions of hepatotoxic agents. However, the mechanism(s) for such resiliency remains unknown. Pilot studies from our laboratory demonstrate that hepatocytes induced to proliferate following the administration of sublethal doses of two model hepatotoxicants (acetaminophen and carbon tetrachloride) have elevated expression of the canalicular ATP-dependent efflux pump for organic anions known as MRP-2, alternatively known as canalicular MRP (cMRP) or c MOAT. We hypothesize that induction of hepatocellular proliferation results in an increased expression of this protein. The overall goal of the studies in this proposal is to better characterize the up-regulation of this transport protein, which could contribute to the resiliency of proliferating hepatoyctes to chemically, induced injury. Our first goal is to examine the temporal alterations in MRP-2 expression and its tissue distribution during hepatocellular regeneration. Then we will determine if induction of hepatocellular replication in vivo using other models of compensatory hyperplasia and direct mitogenesis similarly enhance the expression of MRP-2. The studies outlined in this AREA grant should provide the foundation for future studies intended to elucidate the functional consequences of changes in the expression of this protein in proliferating hepatocytes. We would like to put forward the notion that up-regulation of MRP-2 may be one of several mechanisms by which proliferating hepatocytes acquire resistance to chemical injury.