Mechanisms of Tenofovir Renal Tubular Toxicity

替诺福韦肾小管毒性机制

基本信息

批准号：
7993804
负责人：
JAMES J KOHLER
金额：
$ 5.4万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-01 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7993804
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

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 pathogen- esis 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-expressionand/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.

该职业发展奖提案包括一项研究肾小管机制的计划富马酸替诺福韦二吡呋酯 (TDF) 引起的上皮损伤，TDF 是一种用于治疗 HIV/艾滋病的 NtRTI。这该奖项将帮助候选人詹姆斯·科勒博士成为一名独立调查员。他的小学导师 William Lewis 博士和共同导师 Drs。肯尼思·伯恩斯坦、杰夫·桑德斯、兰迪·亨尼格、凡妮莎 Bijol 和 Raymond Schinazi 是肾脏病理学或 HIV 研究领域的专家，拥有广泛的研究经验。辅导经验。该计划为高质量的研究和教学提供了一个结构化的环境通过埃默里大学医学院和奖学金计划进行培训。该部门埃默里医学院病理学和埃默里艾滋病研究中心全力支持他的申请。拟议的计划定义了 TDF 肾小管转运和线粒体！病原体的生物发生- TDF毒性的产生。 TDF 的肾小管毒性是一种公认的副作用，但尚未完全了解机制。由于 HIV 感染与肾病（HIVAN；一种肾小球疾病）相关，并且 TDF 一种重要的抗逆转录病毒药物，具有肾小管损伤的副作用，从逻辑上讲，肾小管和肾小球损伤（分别来自 TDF 和 HIVAN）可能是累加性或协同性的肾脏相关性损伤艾滋病毒/艾滋病的并发症。这是基础研究的临床原理。可行的假设指出：TDF 通过与 dAdo 竞争磷酸化而引起肾小管中的线粒体毒性。天然 dAdo 和 TDF 的丰度受 DNC、OAT-1 或 MRP4。磷酸化 TDF 与 dATP 竞争作为 pol-gamma（mtDNA 复制酶）的底物，导致 mtDNA 耗竭、电子传递和氧化磷酸化缺陷以及线粒体提出这些目标：1) 确定 TDF 对肾小管的毒性机制有或没有 HIVAN 的上皮线粒体； 2) 确定DNC、OAT1或MRP4肾小管转运 TDF磷酸盐； 3) 确定基于 TDF 的组合的肾小管毒性机制抗逆转录病毒药物。鼠肾靶向转基因过表达和/或 DNC、OAT-1 或 MRP4 消融提供一系列“功能获得”或“功能丧失”复杂的生物工具来定义体内 TDF 肾脏毒性。结果将为 TDF 诱导的肾毒性提供新的见解。