Mechanisms of Tenofovir Renal Tubular Toxicity

替诺福韦肾小管毒性机制

基本信息

批准号：
7586621
负责人：
JAMES J KOHLER
金额：
$ 11.68万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-03-15 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7586621
关键词：
Ablation Acquired Immunodeficiency Syndrome Adverse effects Anions Anti-Retroviral Agents Award Biogenesis Biological CCL21 gene Cadherins Cells Chronic Kidney Failure Clinical Complex Disease Dissection Doctor of Philosophy Dose Drug Combinations Drug Kinetics Electron Transport Environment Epithelial Epithelial Cells Epithelium Evaluation Event Family Fellowship Program Functional disorder Gender Human Infection Injury K-Series Research Career Programs Kidney Kidney Diseases Kidney Failure Knock-out Knockout Mice Lasers Mentors Microscopic Mitochondria Mitochondrial DNA Molecular Mus Nucleosides Nucleotides Organic Anion Transporters Outcome Oxidative Phosphorylation Pathogenesis Pathology Phosphorylation Proteins Proximal Kidney Tubules Renal glomerular disease Renal tubule structure Research Research Personnel Reverse Transcriptase Inhibitors Sampling Series Silicon Dioxide Structure Tenofovir Tenofovir disoproxil fumarate Time Tissues Toxic effect Training Transgenic Mice Transgenic Organisms Tubular formation Universities Virus Western Blotting Work Zidovudine antiretroviral therapy base experience fialuridine gain of function in vivo inorganic phosphate insight kidney cell loss of function medical schools member nucleotide analog pathogen polypeptide programs promoter protein transport renal tubular transport replicase research study standard of care tool treatment duration

项目摘要

DESCRIPTION (provided by applicant): This career development award proposal includes a plan to investigate mechanisms of renal tubular epithelial damage caused by tenofovir disoproxil fumarate (TDF), an NtRTI used to treat HIV/AIDS. This award will help the candidate James Kohler, Ph.D., to become an independent investigator. His primary mentor, Dr. William Lewis, and co-mentors Drs. Kenneth Bernstein, Jeff Sands, Randy Hennigar, Vanesa Bijol, and Raymond Schinazi are experts in the field of renal pathology or HIV research with extensive mentoring experience. The plan provides a structured environment for high-quality research and didactic training through the Medical School and Fellowship Program at Emory University. The Department of Pathology, Emory School of Medicine and Emory Center for AIDS Research fully support his application. The proposed program defines TDF renal tubular transport and mitochondria! biogenesis in the pathogenesis of TDF toxicity. Renal tubular toxicity from TDF is a recognized side effect with incompletely understood mechanisms. Since HIV infection is associated with nephropathy (HIVAN; a glomerular disease), and TDF is an important antiretroviral with the side effect of tubular injury, it follows logically that both tubular and glomerular injuries (from TDF and HIVAN, respectively) could be additive or synergistic kidney-related complications in HIV/AIDS. This is the clinical rationale for the basic studies. The WORKING HYPOTHESIS states: TDF causes mitochondrial toxicity in renal tubules by competing with dAdo for phosphorylation. Abundance of native dAdo and of TDF is regulated cytoplasmically and mitochondrially by DNC, OAT-1, or MRP4. Phosphorylated TDF competes with dATP as a substrate for pol-gamma (the mtDNA replicase), resulting in mtDNA depletion, deficient electron transport and oxidative phosphorylation, and mitochondrial and cellular dysfunction. These AIMS are proposed:1) To define mechanisms of TDF toxicity on renal tubular epithelial mitochondria with or without HIVAN; 2) To determine DNC, OAT1, or MRP4 renal tubular transport of TDF phosphates; and 3) To determine the mechanisms of renal tubular toxicity of TDF-based combination antiretrovirals. Murine renal targeted transgenic over-expression and/or ablation of DNC, OAT-1 or MRP4 offer a series of "gain of function" or "loss of function" sophisticated biological tools to define in vivo TDF toxicity in kidney. Results will provide new insights into TDF-induced renal toxicity.

描述（由申请人提供）：该职业发展奖项提案包括一项计划，研究由Tenofovir Disoproxy fumarate（TDF）引起的肾小管上皮损害的机制，这是一种用于治疗HIV/AIDS的NTRTI。该奖项将帮助候选人詹姆斯·科勒（James Kohler）博士成为独立调查员。他的主要导师威廉·刘易斯（William Lewis）博士和联合委托人博士。肯尼斯·伯恩斯坦（Kenneth Bernstein），杰夫·桑兹（Jeff Sands），兰迪·亨尼加（Randy Hennigar），凡妮·贝乔尔（Vanesa Bijol）和雷蒙德·辛纳齐（Raymond Schinazi）是肾脏病理学或艾滋病毒研究领域的专家，具有丰富的指导经验。该计划为通过埃默里大学的医学院和奖学金计划提供了一个结构化的环境，用于高质量研究和教学培训。埃默里医学院和埃默里艾滋病研究中心病理学系充分支持他的应用。拟议的程序定义了TDF肾小管运输和线粒体！ TDF毒性发病机理中的生物发生。 TDF的肾小管毒性是公认的副作用，其机制未完全理解。由于HIV感染与肾病有关（Hivan;肾小球疾病），而TDF是重要的抗逆转录病毒，具有肾小管损伤的副作用，因此从逻辑上讲，逻辑上，肾小管和肾小球损伤（分别来自TDF和Hivan）可以是附加性或肾小球损伤。艾滋病毒/艾滋病中与肾脏相关的并发症。这是基础研究的临床原理。工作假设指出：TDF通过与DADO竞争磷酸化来引起肾小管中的线粒体毒性。 DNC，OAT-1或MRP4对天然DADO和TDF的丰度受到细胞质和线粒的调节。磷酸化的TDF与DATP作为Pol-Gamma（mtDNA复制酶）的底物竞争，导致mtDNA耗竭，缺乏电子传输和氧化磷酸化以及线粒体和细胞功能障碍。提出了这些目的：1）定义TDF毒性在肾小管上皮线粒体上具有或不带Hivan的机制； 2）确定TDF磷酸盐的DNC，OAT1或MRP4肾小管转运； 3）确定基于TDF组合抗逆转录病毒的肾小管毒性的机制。 DNC，OAT-1或MRP4的鼠肾脏靶向转基因过表达和/或消融提供了一系列“功能的增长”或“功能丧失”或“功能丧失”，以定义肾脏中体内TDF毒性的精致生物学工具。结果将为TDF诱导的肾脏毒性提供新的见解。