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。 阿霉素 (DOX) 是一种广泛应用的癌症治疗药物，是导致不可逆癌症的重要因素 心肌病。有证据表明 DOX 治疗诱发的心肌病与血压升高有关 线粒体 DNA (mtDNA) 突变水平。线粒体（mt）对于心肌细胞的生理学至关重要， 因此，mtDNA 突变影响心肌细胞功能并与心肌细胞功能相关也就不足为奇了。 心肌病。然而，尚不清楚 mtDNA 突变负荷是否或如何导致心肌病。这个 这个问题因以下事实而令人困惑：疾病的表现可能取决于疾病的异质性 给定细胞或细胞群中的“患病”线粒体与“健康”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 衍生的心肌细胞来解决 mtDNA 基因变异或 突变影响 DOX 诱发的心肌病。该提案的总体目标是解决是否 特定 mtDNA 突变和/或突变与非突变 mtDNA 的比例应视为风险 DOX 治疗后心肌病发生的因素或被解释为病因。 我假设 mtDNA 突变是在接受癌症治疗的患者中诱导或选择的，并且 mtDNA 突变及其异质负荷在癌症后发生的心肌病中起着致病作用 DOX 等治疗。我们将通过基于患者的关联研究来检验这一假设：1）挖掘 100,000 个基因组计划数据库可识别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/异质负荷。除此之外，我还会表演 在 iPSC 衍生中使用表型和遗传高通量筛选方法进行功能研究 心肌细胞以确定 2) DOX 是从头诱导还是选择预先存在的 mtDNA 突变， 3）诱导或选择的mt突变是否直接导致肌病。 这项调查的结果应该能够解决 DOX 是否会导致突变或选择先前存在的问题。 变体，并应通过回答“患者是否应该这样做”这一关键问题来帮助为临床决策提供信息 DOX 治疗后是否要仔细监测某些 mtDNA 变异的异质性？”此外，还应该 为我未来的研究生涯奠定基础，我想制定治疗策略 潜在地改变癌症治疗后有患心肌病风险的患者的 mtDNA 异质性。 因此，重要的是要确定患者生活中可能有助于创造或增加的选择事件。 mtDNA 突变的存在，特别是因为目前尚无针对 mt 疾病的治疗方法。

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.