MECHANISM-BASED MODELING OF ALPHA-2MU-GLOBULIN ACCUMULATION IN MALE RAT KIDNEY

雄性大鼠肾脏中 ALPHA-2MU 球蛋白积累的基于机制的建模

• 批准号: 6162330
• 负责人: R L MELNICK
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6162330
• 关键词: alpha globulin; biological models; kidney disorder; kidney metabolism; kidney pharmacology; laboratory rat; liver metabolism; male; model design /development; protein metabolism; renal tubular transport

Summary of Work: The a2u-globulin hypothesis has been used to discount the human relevance of kidney tumors induced in male rats. We are examining quantitative linkages among critical biological processes in this hypothesis by model simulations using published data. The model includes parameter values that describe the toxicokinetics of the binding ligand, its interaction with a2u-globulin, secretion of a2u-globulin from the liver, resorption of a2u-globulin into proximal tubule epithelial cells, and degradation of the ligand-a2u-globulin complex. A preliminary model of the effects of 2,2,4-trimethylpentan-2-ol (TMP) on the accumulation of a2u-globulin in the male rat kidney showed that this effect cannot be due solely to inhibition of proteolysis. The model suggests that a2u-globulin ligands may increase the hepatic synthesis of this protein and that degradation of unbound a2u-globulin may also be reduced as a consequence of accumulation of the ligand.

工作总结：a2 u-球蛋白假说已被用于贴现 在雄性大鼠中诱导的肾脏肿瘤的人类相关性。我们 研究关键生物过程之间的定量联系， 这一假设是通过使用已公布的数据进行模型模拟得出的。 模型 包括描述结合的毒性的参数值 配体，与α 2u-球蛋白的相互作用，α 2u-球蛋白的分泌 来自肝脏的α 2u-球蛋白再吸收进入近端小管 上皮细胞和配体-α 2u-球蛋白复合物的降解。一 2，2，4-三甲基戊-2-醇（TMP）对 雄性大鼠肾脏中α 2u-球蛋白的积累表明， 作用不能仅仅是由于抑制蛋白水解。模型 表明α 2 β-球蛋白配体可能增加肝脏合成α 2 β-球蛋白， 这种蛋白质和未结合α 2 β-球蛋白的降解也可以 由于配体的积累而减少。