Mitochondrial toxicity of AZT-3TC in experimental models

实验模型中 AZT-3TC 的线粒体毒性

• 批准号: 7105121
• 负责人: SALINA M TORRES
• 金额: $ 2.78万
• 依托单位: LOVELACE BIOMEDICAL & ENVIRONMENTAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7105121
• 关键词: AIDS therapy; DNA damage; antiAIDS agent; biomarker; cellular pathology; combination chemotherapy; developmental disease /disorder; echocardiography; embryo /fetus drug adverse effect; embryo /fetus toxicology; gene mutation; heart disorder; laboratory mouse; lamivudine; longitudinal animal study; lymphocyte; mitochondrial DNA; mitochondrial disease /disorder; placental transfer; predoctoral investigator; reverse transcriptase inhibitors; zidovudine

DESCRIPTION (provided by applicant): Nucleoside reverse transcriptase inhibitors (NRTIs) when given in combination are highly effective in reducing the vertical transmission of HIV-1 from mother to infant; however, these drugs may impose a risk for cancer and mitochondria! disease later in life in exposed children. The objective of this study is to determine the relative impact of AZT, 3TC, and AZT-3TC on mitochondrial structure and function in human lymphoblastoid cells exposed in vitro and in lymphocytes and hearts of mice exposed transplacentally. The long-term objective is to determine whether NRTI-induced mtDNA mutations play a critical role in temporal changes in mitochondrial structure and function in heart and other tissues/cell types. Two specific aims will be accomplished: 1. to determine the relative ability of AZT-3TC to induce toxicity by defining genotoxicity, mutagenicity and altered mitochondrial structure and function 2. To compare, at birth and 3 months of age, mitochondrial toxicity in cardiac tissue and lymphocytes following transplacental exposure of female B6C3F1 mice to AZT, 3TC or AZT-3TC.

描述（由申请人提供）：组合中给出的核苷逆转录酶抑制剂（NRTIS）在减少HIV-1从母亲到婴儿的垂直传播方面非常有效；但是，这些药物可能会出现癌症和线粒体的风险！暴露儿童的疾病后来生活。这项研究的目的是确定AZT，3TC和AZT-3TC对人淋巴母细胞中线粒体结构和功能的相对影响。长期目标是确定NRTI诱导的mtDNA突变是否在心脏和其他组织/细胞类型的线粒体结构的时间变化和功能中是否起关键作用。 Two specific aims will be accomplished: 1. to determine the relative ability of AZT-3TC to induce toxicity by defining genotoxicity, mutagenicity and altered mitochondrial structure and function 2. To compare, at birth and 3 months of age, mitochondrial toxicity in cardiac tissue and lymphocytes following transplacental exposure of female B6C3F1 mice to AZT, 3TC or AZT-3TC。