Renal Disposition in NASH

NASH 中的肾脏配置

• 批准号: 10331779
• 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
• 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/10331779
• 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; simple steatosis; systemic inflammatory response; toxicant; volunteer

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.

项目总结 肝病和肾功能之间的相互关系正变得越来越多的研究，因为肝- 衍生的全身性炎症会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，因为这些变化可能会扰乱正常的新陈代谢和 消除32%的市场上依赖肾功能排泄的治疗药物。在肝脏中 影响肾脏生理的疾病是非酒精性脂肪性肝病(NAFLD)，其特征是一系列 调节从单纯性脂肪变性向非酒精性脂肪性肝炎(NASH)转变的机械性事件， 其中包括炎症性事件。我们的实验室已经确定了NASH诱导的几种药物的表型转换 代谢酶和转运蛋白，显著改变某些药物的药代动力学 以及外源生物。有趣的是，在对NASH的各种啮齿动物模型的剖析研究中，我们还发现 NASH诱导的肾脏运输蛋白的表型转换，这一现象也有助于改变 异种基质在体内的药代动力学。到目前为止，还没有发表过研究人类 NASH相关的肾脏药物转运体的表型转换，这将是我们在这篇文章中讨论的第一个项目 申请。我们的中心假设是NASH改变了主要肾脏药物的表达和功能 转运体，从而增加了药物不良反应和环境毒性的风险 NASH患者。我们的研究设计不仅寻求识别特定肾脏转运体的表型转换 在NASH中，还可以精确定位相关的分泌途径，以更好地缩小改变的机制 某些治疗药物和环境污染物的药代动力学。我们的目标是：1)确定 NASH患者肾脏转运蛋白表达和定位的变化，2)决定 啮齿动物个体分泌途径的功能变化及其导致的环境毒性 NASH模型，以及3)确定NASH对GFR的影响，并选择人类患者的分泌途径。 通过完成这些目标，我们将能够识别出存在较大不良药物风险的药物类别 NASH患者的活动。