权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

雄性大鼠肾脏中 ALPHA-2U-球蛋白积累的基于机制的建模

基本信息

批准号：
6290099
负责人：
RONALD L MELNICK
金额：
--
依托单位：
NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
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/6290099
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

项目摘要

Summary of Work: The alpha-2u-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 alpha-2u-globulin, secretion of alpha-2u-globulin from the liver, resorption of alpha-2u-globulin into proximal tubuleepithelial cells, and degradation of the ligand-alpha- 2u-globulin complex. A physiological model of the effects of 2,2,4- trimethylpentan-2-ol (TMP-2-OH) on the accumulation of alpha-2u- globulin in the male rat kidney showed that this effect cannot be due solely to inhibition of proteolysis. The model could reproduce time course data of blood and kidney TMP-2-OH and renal alpha-2u-globulin concentrations if a transient increase in hepatic synthesis of alpha- 2u-globulin, stimulated by liganded alpha-2u-globulin in the blood, was assumed. The model suggests that alpha-2u-globulin ligands may increase the hepatic synthesis of this protein. The model predicts greater delivery of ligand to the kidney and greater renal production of potentially toxic metabolites than would occur if alpha-2u-globulin was absent. The analysis indicates that induced lysosomal activity and increased production of toxic metabolites may contribute to the nephrotoxicity of alpha-2u-globulin ligands. - kidney cancer, alpha-2u- globulin, male rats, trimethylpentane, 2,4,4-trimethyl-2-pentanol, unleaded gasoline

工作总结：α-2u-球蛋白假说已被用来降低雄性大鼠肾肿瘤与人类的相关性。我们正在通过使用已发表的数据进行模型模拟来研究这一假设中关键生物过程之间的定量联系。该模型包括描述结合配体的毒代动力学、其与 α-2u-球蛋白的相互作用、肝脏分泌 α-2u-球蛋白、近端小管上皮细胞吸收 α-2u-球蛋白以及配体-α-2u-球蛋白复合物降解的参数值。 2,2,4-三甲基戊-2-醇 (TMP-2-OH) 对雄性大鼠肾脏中 α-2u-球蛋白积累影响的生理模型表明，这种影响不能仅仅归因于抑制蛋白水解。如果假设血液中配体 α-2u-球蛋白刺激肝脏合成 α-2u-球蛋白短暂增加，则该模型可以重现血液和肾脏 TMP-2-OH 和肾 α-2u-球蛋白浓度的时程数据。该模型表明 α-2u-球蛋白配体可能会增加这种蛋白质的肝脏合成。该模型预测，与不存在 α-2u-球蛋白的情况相比，配体向肾脏的输送量更大，肾脏产生的潜在毒性代谢物也更多。分析表明，诱导的溶酶体活性和有毒代谢物产生的增加可能导致 α-2u-球蛋白配体的肾毒性。 - 肾癌、α-2u-球蛋白、雄性大鼠、三甲基戊烷、2,4,4-三甲基-2-戊醇、无铅汽油