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，肝细胞正在响应主动复制 进行有丝分裂刺激或在化学后再生期间 毒性对肝毒性剂的作用有抵抗力。但是， 这种弹性的机制仍然未知。来自我们的试点研究 实验室表明，肝细胞在 给予两种模型肝毒性剂的余量（乙酰氨基酚） 和四氯化碳）具有升高的口腔表达 ATP依赖性外排泵，用于有机阴离子，称为MRP-2 称为口腔MRP（CMRP）或C护城河。我们假设该诱导 肝细胞增殖导致这种表达增加 蛋白质。该提案中研究的总体目标是更好 表征该转运蛋白的上调，可以 有助于化学上增殖的肝脏的弹性， 诱发受伤。我们的第一个目标是检查MRP-2的时间变化 在肝细胞再生过程中的表达及其组织分布。然后 我们将确定使用肝细胞复制在体内是否使用 其他模型的补偿性增生和直接有丝分裂发生类似 增强MRP-2的表达。该领域概述的研究应 为未来的研究提供基础，旨在阐明功能 该蛋白表达的变化在增殖中的后果 肝细胞。我们想提出这样的观念 MRP-2可能是增殖肝细胞的几种机制之一 获得对化学损伤的抵抗力。