MRP 2 (CMOAT) EXPRESSION IN HEPATOCELLULAR PROLIFERATION

MRP 2 (CMOAT) 在肝细胞增殖中的表达

• 批准号: 6024453
• 负责人: Jose E Manautou
• 金额: $ 10.69万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6024453
• 关键词: acetaminophen; carbon tetrachloride; gene induction /repression; laboratory mouse; liver cells; liver regeneration; liver toxic disorder; membrane transport proteins

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.

众所周知，肝细胞在响应过程中进行主动复制 有丝分裂刺激或化学后再生过程中 毒性对肝毒性药物的作用具有抵抗力。然而， 这种弹性的机制仍然未知。我们的试点研究 实验室证明，肝细胞在以下条件下诱导增殖： 给予亚致死剂量的两种模型肝毒药物（对乙酰氨基酚 和四氯化碳）使小管的表达升高 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。我们假设归纳 肝细胞增殖导致该蛋白的表达增加 蛋白质。本提案中研究的总体目标是更好地 表征这种转运蛋白的上调，这可以 有助于增殖肝细胞对化学物质的弹性， 诱发损伤。我们的第一个目标是检查 MRP-2 的时间变化 肝细胞再生过程中的表达及其组织分布。然后 我们将确定是否使用以下方法诱导体内肝细胞复制 其他代偿性增生和直接有丝分裂的模型类似 增强MRP-2的表达。该 AREA 补助金中概述的研究应该 为未来的研究奠定基础，旨在阐明功能 该蛋白在增殖中表达变化的后果 肝细胞。我们想提出一个概念，即上调监管 MRP-2可能是肝细胞增殖的多种机制之一 获得对化学损伤的抵抗力。