In utero NRTIs & mtDNA Changes in Cardiac/Vascular Cells

子宫内 NRTI

基本信息

批准号：
6923680
负责人：
VERNON E WALKER
金额：
$ 67.05万
依托单位：
LOVELACE BIOMEDICAL & ENVIRONMENTAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-09-30 至 2007-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Potential health risks associated with the clinical use of nucleoside analogue reverse transcriptase inhibitors (NRTIs) exist because the molecular basis for their effectiveness also actuates their potential toxicities. Current research suggests that one of the manifestations of this toxicity is mitochondrial damage leading to cardiac disease. The purpose of this project is to determine the nature and extent of NRTI-induced damage in mitochondria by evaluating the types and frequencies of mutations induced in mitochondrial tRNA genes of human cells exposed in vitro, and in tissues of mouse and human exposed transplacentally. The impact of these mutations upon markers of mitochondrial function (EM studies of mitochondrial structure, mtDNA depletion studies, and OXPHOS/COX enzyme assays) will be evaluated, using a modified parallelogram approach, in human lymphocytes exposed in vitro, in heart cells and lymphocytes of mice exposed in utero, and in lymphocytes and umbilical cord tissue of human infants exposed in utero. Short-term and long-term studies will be conducted to evaluating the persistence of mitochondrial DNA mutations and mitochondrial dysfunction in rodents and children exposed in utero. Commonly used NTRIs (AZT, 3TC, and d4T), either alone or in combination, will be evaluated. Preliminary studies will be conducted to determine the human-equivalent dose necessary to replicate in vivo in the mouse the plasma levels of AZT found in human children. The long range goals of this project are i) to determine the relationship between the types and frequencies of mtDNA mutations and alterations in mitochondrial function, and ii) to determine the relative potency of individual NRTIs, and/or combinations of commonly used NRTIs, to induce deleterious mitochondrial damage. Elucidation of the mechanisms underlying NRTI-induced mitochondrial damage will benefit HIV-infected patients taking NRTIs to control infection, HIV-exposed individuals who take NRTIs prophylactically to prevent HIV infection, and children receiving perinatal NRTIs to prevent HIV infection.

描述（由申请人提供）：与临床使用核苷类似物逆转录酶抑制剂（NRTIS）有关的潜在健康风险，因为其有效性的分子基础也可以促进其潜在的毒性。当前的研究表明，这种毒性的表现之一是导致心脏病的线粒体损害。该项目的目的是通过评估在体外暴露于人类细胞的线粒体TRNA基因以及小鼠和人类暴露于移植的人体组织中诱导的突变的类型和频率来确定NRTI-I诱导的线粒体损伤的性质和程度。这些突变对线粒体功能标记的影响（线粒体结构的EM研究，mtDNA耗竭研究和Oxphos/oxphos/oxphos/cox酶测定）将使用修改的平行四边形方法在人类淋巴细胞中进行的，在心脏细胞和淋巴细胞中的人类淋巴细胞中，在人类的淋巴细胞中，在人类淋巴细胞中，并在Hearm -explocy of Heart Cells和lymphocytes中，并在Utermphocy and themphocy and和umphocytiles中及在子宫内暴露的人类婴儿的组织。将进行短期和长期研究，以评估啮齿动物和子宫内暴露的儿童线粒体DNA突变和线粒体功能障碍的持续性。将评估常用的NTRI（AZT，3TC和D4T），无论是单独或组合的）。将进行初步研究，以确定在小鼠中复制体内复制的人类等效剂量。该项目的远距离目标是i）确定mtDNA突变的类型和频率与线粒体功能的变化之间的关系，以及ii）确定单个NRTI的相对效力，以及/或常用的NRTIS的组合，以诱导有害的线粒体损伤。阐明NRTI诱导的线粒体损伤的机制将使受HIV感染的患者受益于接受NRTI的患者控制NRTIS，以控制感染，HIV暴露的个体预防性接受NRTIS，以预防HIV感染，以预防HIV感染，并接受perinate核NRTIS感染，以预防HIV。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

In utero exposure of female CD-1 mice to AZT and/or 3TC: II. Persistence of functional alterations in cardiac tissue.

DOI：
10.1007/s12012-010-9065-z
发表时间：
2010-06
期刊：
CARDIOVASCULAR TOXICOLOGY
影响因子：
3.2
作者：
Torres, Salina M.;Divi, Rao L.;Walker, Dale M.;McCash, Consuelo L.;Carter, Meghan M.;Campen, Matthew J.;Einem, Tracey L.;Chu, Yvonne;Seilkop, Steven K.;Kang, Huining;Poirier, Miriam C.;Walker, Vernon E.
通讯作者：
Walker, Vernon E.

In utero exposure of female CD-1 Mice to AZT and/or 3TC: I. Persistence of microscopic lesions in cardiac tissue.

DOI：
10.1007/s12012-010-9061-3
发表时间：
2010-03
期刊：
CARDIOVASCULAR TOXICOLOGY
影响因子：
3.2
作者：
Torres, Salina M.;March, Thomas H.;Carter, Meghan M.;McCash, Consuelo L.;Seilkop, Steven K.;Poirier, Miriam C.;Walker, Dale M.;Walker, Vernon E.
通讯作者：
Walker, Vernon E.