Renal Disposition in NASH

NASH 中的肾脏配置

基本信息

批准号：
10094060
负责人：
Nathan J Cherrington
金额：
$ 48.21万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10094060
关键词：
ABCG2 gene Address Adverse drug event Affect Animals Biopsy Body Weight decreased Brush Border C-reactive protein Carrier Proteins Clinical Data Collection Diagnosis Disease Dose Drug Kinetics Drug toxicity Environmental Pollution Enzymes Event Excretory function Extrahepatic Female Filtration Functional disorder Glomerular Filtration Rate Goals Hepatic Human Hypoglycemic Agents Individual Inflammation Mediators Inflammatory Interferons Investigation Iohexol Kidney Liver Liver Dysfunction Liver diseases Mediating Metabolism Metformin Modeling Morbid Obesity Operative Surgical Procedures Organ Outcome POU2F1 gene POU2F2 gene Pathology Pathway interactions Patients Pharmaceutical Preparations Phenotype Physiology Plasma Play Predisposition Process Publishing Rattus Renal Tissue Renal clearance function Renal function Research Research Design Risk Rodent Model Role Series Standardization Stress Surveys Testing Therapeutic Time Toxic Environmental Substances Toxic effect Treatment Efficacy Tubular formation Urine Vesicle Xenobiotics adefovir adverse drug reaction appropriate dose bariatric surgery basolateral membrane blood filtration clinically relevant design diabetic drug efficacy drug metabolism hydrophilicity in vivo individual patient inter-individual variation interest liver metabolism male non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel obese patients precision medicine response systemic inflammatory response toxicant volunteer

项目摘要

PROJECT SUMMARY The interrelation between liver disease and kidney function is becoming increasingly researched, as hepatic- derived systemic inflammation can have a profound effect on the physiology of the kidney. This is a vital factor to consider with respect to precision medicine, as these changes can disrupt the proper metabolism and elimination of the 32% of marketed therapeutics that rely upon renal function for excretion. Among the liver diseases that affect renal physiology is nonalcoholic fatty liver disease (NAFLD), characterized by a series of mechanistic events that mediate the transition from simple steatosis to nonalcoholic steatohepatitis (NASH), which include inflammatory events. Our lab has identified NASH-induced phenotypic conversions of several drug metabolizing enzyme and transport proteins that significantly alter the pharmacokinetic profiles of certain drugs and xenobiotics. Interestingly, in a profiling study of various rodent models of NASH, we have also identified NASH-induced phenoconversion of renal transport proteins, a phenomenon that also contributes to altered pharmacokinetics of xenobiotic substrates in vivo. To date, no studies have been published examining human NASH-related phenoconversion of renal drug transporters, and that will be the first item we address in this application. Our central hypothesis is that NASH alters the expression and function of major renal drug transporters, thereby increasing the risk of adverse drug reactions and environmental toxicities in patients with NASH. Our study design seeks not only to identify phenoconversion of specific renal transporters in NASH, but also to pinpoint the associated secretory pathways to better narrow down mechanisms of altered pharmacokinetics for certain therapeutics and environmental contaminants. Our aims are to: 1) Determine the changes in expression and localization of renal transporters in human NASH patients, 2) Determine the functional changes in individual secretion pathways and resulting potential for environmental toxicity in a rodent model of NASH, and 3) Determine the impact of NASH on GFR and select secretion pathways in human patients. By completing these aims, we will be able to identify classes of drugs that present a greater risk of adverse drug events for NASH patients.

项目摘要肝病和肾功能之间的相互关系正在越来越多地研究，因为衍生的全身性炎症可以对肾脏的生理产生深远的影响。这是一个至关重要的因素考虑到精确医学，因为这些变化会破坏适当的新陈代谢和消除依赖肾功能排泄的32％的销售治疗剂。在肝脏中影响肾脏生理的疾病是非酒精性脂肪肝疾病（NAFLD），其特征是一系列机械事件介导了从简单脂肪变性到非酒精性脂肪性肝炎（NASH）的过渡，其中包括炎症事件。我们的实验室已经确定了NASH诱导的几种药物的表型转化代谢酶和转运蛋白会显着改变某些药物的药代动力学特征和异种生物。有趣的是，在对纳什各种啮齿动物模型的分析研究中，我们还确定了 NASH诱导的肾脏转运蛋白的表现，这种现象也有助于改变体内异生元底物的药代动力学。迄今为止，尚未发表研究人类肾脏药物转运蛋白的NASH相关表现，这将是我们在此解决的第一项应用。我们的中心假设是纳什改变了主要肾脏药物的表达和功能转运蛋白，从而增加了不良药物反应和环境毒性的风险纳什患者。我们的研究设计不仅旨在识别特定肾脏转运蛋白的表现在纳什（Nash 某些治疗学和环境污染物的药代动力学。我们的目标是：1）确定人纳什患者肾脏转运蛋白表达和定位的变化，2）确定啮齿动物中各个分泌途径的功能变化和产生的环境毒性的潜力 NASH的模型，以及3）确定NASH对GFR和SELECT分泌途径对人类患者的影响。通过完成这些目标，我们将能够确定具有更大不良药物风险的药物类别纳什患者的事件。