The role of mitochondrial DNA mutations in chemotherapy induced cardiomyopathy

线粒体DNA突变在化疗引起的心肌病中的作用

• 批准号: 10335058
• 负责人: Alexander Kreymerman
• 金额: $ 3.27万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-03 至 2023-09-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10335058
• 关键词: role; mitochondrial; DNA; mutations; chemotherapy

The role of mitochondrial DNA mutations in chemotherapy induced cardiomyopathy. Doxorubicin(DOX), a broadly applied cancer therapeutic, is a significant contributor to irreversible cardiomyopathy. Evidence suggests that DOX treatment-induced cardiomyopathy is associated with elevated levels of mitochondrial DNA (mtDNA) mutations. Mitochondria (mt) are critical for cardiac myocyte physiology, and it is not surprising, therefore, that mtDNA mutations effect cardiac myocyte function and are associated with cardiomyopathy. However, it is unclear if or how the mtDNA mutation load contributes to cardiomyopathy. This question is confounded by the fact that disease presentation can be dependent on the heterogeneity of “diseased” vs “healthy” mitochondria in a given cell or cell population, known as mitochondrial heteroplasmy. Here, I will use patient genetics and iPSC-derived cardiomyocytes to resolve how mtDNA gene variants or mutations affect DOX-induced cardiomyopathy. The overarching goal of this proposal is to resolve whether specific mtDNA mutations and/or the proportion of mutated vs non-mutated mtDNA should be treated as a risk factor or interpreted as causative in the development of cardiomyopathy after DOX treatment. I hypothesize that mtDNA mutations are induced or selected for in patients treated for cancer and that mtDNA mutations and that their heteroplasmic load plays a causative role in the cardiomyopathy developed after cancer treatments such as DOX. We will test this hypothesis through patient-based association studies: 1) mining the 100,000 Genomes Project database to identify risk factors between cancer treatments, the development of cardiomyopathy, and the presence/heteroplasmic load of specific mtDNA mutations. In addition, I will perform functional studies using phenotypic and genetic high throughput screening approaches in iPSC-derived cardiomyocytes to determine 2) whether DOX induces de novo versus selects for pre-existing mtDNA mutations, and 3) whether induced or selected mt mutations directly cause myopathy. The results of this investigation should resolve whether DOX causes mutations or selects for pre-existing variants, and should help inform clinical decision making by answering the key question of “Should patients that are heteroplasmic for certain mtDNA variants be monitored carefully after DOX treatment?” Moreover, it should lay the groundwork for my future research career, in which I would like to develop therapeutic strategies to potentially alter mtDNA heteroplasmy in patients at risk for developing cardiomyopathy after cancer treatment. Thus, it is important to identify the selection events in a patient’s life that could contribute to creating or increasing the presence of mtDNA mutations, especially since there are no current treatments for mt disease.

线粒体DNA突变在化疗所致心肌病中的作用 阿霉素(DOX)是一种广泛应用的癌症治疗方法，是导致不可逆转的重要因素 心肌病。有证据表明，DOX治疗引起的心肌病与升高有关 线粒体DNA(MtDNA)突变水平。线粒体(Mt)对心肌细胞生理学至关重要， 因此，mtDNA突变影响心肌细胞功能并与 心肌病。然而，目前还不清楚线粒体DNA突变负荷是否或如何导致心肌病。这 一个令人困惑的事实是，疾病的表现可能取决于 在特定的细胞或细胞群体中，“患病的”线粒体与“健康的”线粒体，称为线粒体异质性。 在这里，我将使用患者遗传学和IPSC来源的心肌细胞来解析mtDNA基因变异或 基因突变会影响DOX诱导的心肌病。这项提案的首要目标是解决是否 特定的mtDNA突变和/或突变的mtDNA与非突变的mtDNA的比例应视为风险。 在DOX治疗后发生心肌病的因素或被解释为致病因素。 我假设mtDNA突变是在接受癌症治疗的患者中诱导或选择的，而mtDNA 突变及其异质负荷在癌症后发展的心肌病中起致病作用 多柔比星等治疗。我们将通过基于患者的关联研究来验证这一假设：1)挖掘 100,000基因组计划数据库，以确定癌症治疗之间的风险因素，开发 心肌病，以及特定mtDNA突变的存在/异质负载。此外，我还将表演 应用表型和遗传高通量筛选方法对IPSC来源的功能进行研究 以确定2)DOX是否诱导从头开始，还是选择预先存在的mtDNA突变， (3)是否诱发或选择mt突变直接导致肌病。 这项调查的结果应该能确定DOX是否导致突变或对先前存在的选择 变种，并应有助于通过回答以下关键问题来为临床决策提供信息 在DOX治疗后，是否仔细监测某些mtDNA变异体的异质性？此外，它应该 为我未来的研究生涯奠定基础，在这个职业中，我想制定治疗策略 有可能改变癌症治疗后发生心肌病风险的患者的线粒体DNA异质性。 因此，重要的是确定患者生活中可能有助于创造或增加的选择事件 线粒体DNA突变的存在，特别是因为目前还没有治疗多发性硬化症的方法。