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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

基本信息

批准号：
10469514
负责人：
Alexander Kreymerman
金额：
$ 6.76万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-03 至 2024-03-02
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10469514
关键词：
Address Affect Biology Calcium Cancer Patient Cardiac Cardiac Myocytes Cardiac development Cardiomyopathies Cardiotoxicity Cell Line Cell physiology Cells Childhood Complement DNA Damage 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 base 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 novel therapeutic intervention transcription activator-like effector nucleases

项目摘要

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突变在化疗引起的心肌病中的作用。