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: 10705485
• 负责人: Alexander Kreymerman
• 金额: $ 0.25万
• 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/10705485
• 关键词: Address; Affect; Biology; Calcium; Cancer Patient; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiotoxicity; Cell Line; Cell Separation; Cell physiology; Cells; Childhood; Complement; DNA Sequence Alteration; DNA biosynthesis; Databases; Development; Disease; Doxorubicin; Drug Screening; Etiology; Event; Functional disorder; Gene Mutation; Genes; Genetic; Genome; Goals; Incidence; Individual; Induced Mutation; Investigation; Lead; Libraries; Life; Malignant Neoplasms; Methods; Mining; Mitochondria; Mitochondrial DNA; Mitochondrial Diseases; Modeling; Monitor; Mutate; Mutation; Myocardial dysfunction; Myopathy; Nuclear; Patients; Phenotype; Physiology; Play; Population; Production; Reactive Oxygen Species; Research; Risk; Risk Factors; Role; Solid; Survivors; Testing; Therapeutic; Time; Training; Variant; cancer therapy; career; chemotherapy; clinical decision-making; design; disease heterogeneity; drug discovery; functional genomics; genetic variant; heteroplasmy; high throughput screening; induced pluripotent stem cell; induced pluripotent stem cell derived cardiomyocytes; knowledge base; leukemia; mitochondrial DNA mutation; mitochondrial dysfunction; mutation correction; novel therapeutic intervention; transcription activator-like effector nucleases; tumor

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突变在化疗诱发心肌病中的作用 多柔比星（DOX）是一种广泛应用的癌症治疗剂，是不可逆的肿瘤转移的重要贡献者。 心肌病有证据表明，DOX治疗诱导的心肌病与升高的 线粒体DNA（mtDNA）突变水平。线粒体（mt）对心肌细胞的生理功能至关重要， 因此，线粒体DNA突变影响心肌细胞功能并与 心肌病然而，目前尚不清楚mtDNA突变负荷是否或如何导致心肌病。这 问题是混淆的事实，即疾病的表现可以依赖于异质性， 在给定的细胞或细胞群体中，“患病”与“健康”线粒体的差异被称为线粒体异质性。 在这里，我将使用患者遗传学和iPSC衍生的心肌细胞来解决mtDNA基因变异或 基因突变会影响DOX诱导的心肌病本提案的总体目标是解决以下问题： 特定的mtDNA突变和/或突变与非突变mtDNA的比例应被视为风险 在DOX治疗后心肌病的发展中， 我推测，在接受癌症治疗的患者中，mtDNA突变是诱导或选择性的， 突变，并且它们的异质性负荷在癌症后发生的心肌病中起着致病作用。 如DOX治疗。我们将通过基于患者的关联研究来检验这一假设：1）挖掘 10万个基因组项目数据库，以确定癌症治疗之间的风险因素， 心肌病和特定mtDNA突变的存在/异质性负荷。另外，我会表演 使用表型和遗传高通量筛选方法在iPSC衍生的细胞中进行功能研究 心肌细胞以确定2）DOX是否诱导从头还是选择预先存在的mtDNA突变， 和3）是否诱导或选择的MT突变直接引起肌病。 这项调查的结果应该解决DOX是否导致突变或选择预先存在的突变。 变异，并应通过回答“患者是否应该 在DOX治疗后，是否应该仔细监测某些mtDNA变异的异质性？”此外，它应该 为我未来的研究生涯奠定基础，我想开发治疗策略， 可能改变癌症治疗后发生心肌病风险患者的mtDNA异质性。 因此，重要的是要确定患者生活中的选择事件，这些选择事件可能有助于创造或增加患者的生活质量。 线粒体DNA突变的存在，特别是因为目前没有治疗mt疾病的方法。