Mechanistic insights into the role of mitochondrial iron in doxorubicin-induced cardiomyopathy using human induced pluripotent stem cells

使用人类诱导多能干细胞深入了解线粒体铁在阿霉素诱导的心肌病中的作用

基本信息

  • 批准号:
    10577780
  • 负责人:
  • 金额:
    $ 40万
  • 依托单位:
  • 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:
    2020-03-15 至 2025-02-28
  • 项目状态:
    未结题

项目摘要

The clinical use of doxorubicin (DOX, and anticancer drug) is limited due to its cardiotoxic side effects. The mechanism of DOX-induced cardiotoxicity (DIC) is not totally understood. We recently showed that DOX causes mitochondrial (as opposed to total cellular) iron accumulation, and that a reduction in mitochondrial iron leads to protection against DIC. However, these studies were predominantly performed in vitro and in animal models, and it is not clear whether higher mitochondrial iron contributes to DIC susceptibility in patients. To extend these findings beyond animal models, we have established several lines of human induced pluripotent stem cell- derived cardiomyocytes (hiPSC-CM) from patients who either experienced DIC (DIC-CM) or did not have cardiotoxicity (noDIC-CM) after exposure to DOX, and showed that they recapitulate the patients’ phenotype in vitro, and that they are susceptible to a special form of iron-mediated cell death called “ferroptosis”. Using RNA- seq, we have also identified a number of mitochondrial iron genes to be altered in DIC samples after DOX treatment. Finally, we have demonstrated that hiPSC-CM from DIC patients display elevated mitochondrial iron after DOX exposure. Our central hypothesis is that mitochondrial iron plays a key role in the susceptibility to DIC in humans, and that a reduction in mitochondrial iron (either by iron chelators or by modulation of genes involved in mitochondrial iron homeostasis) alter cardiomyocyte susceptibility to DOX. We also hypothesize that DOX clearance from subcellular compartments is regulated by mitochondrial iron through mitophagy, and that this process is impaired in DIC. In Aim 1, we will determine whether DIC-CM are more susceptible to DOX toxicity due to mitochondrial iron accumulation, and that a reduction in mitochondrial iron improves cell viability in these cells. We will modulate mitochondrial iron in DIC-CM and noDIC-CM using mitochondrial permeable iron chelators (including new chelators identified in our lab), followed by exposure to DOX and assessment of ferroptosis and cell viability. In Aim 2, we will determine whether modulation of mitochondrial iron-related genes identified in our RNA-seq analysis alters susceptibility to DOX. Our studies demonstrated that mRNA levels of ABCB7 and ABCB8 (proteins that mediate mitochondrial iron export) and MFRN2 (a mitochondrial iron importer) are altered with DOX treatment. We will delete ABCB7 or ABCB8 in hiPSC from noDIC (which would result in an increase in mitochondrial iron) and MFRN2 in hiPSC from DIC (resulting in a reduction in mitochondrial iron) using CRISPR-Cas9, followed by generation of hiPSC-CM, exposure to DOX, and assessment of cell viability. Finally, in Aim 3, we will determine whether mitochondrial iron regulates DOX clearance and that inherent defects in DOX clearance promotes susceptibility to DIC. We will assess DOX clearance, mitochondrial dynamics and mitophagy in noDIC-CM and DIC-CM after DOX and in the presence and absence of iron chelators, and with modulation of mitochondrial iron genes. We will also assess DOX clearance and mitophagy in the hearts of Abcb8 knockout and transgenic mouse models after DOX.
阿霉素(DOX和抗癌药物)的临床应用因其心脏毒性副作用而受到限制。这个 DOX致心脏毒性(DIC)的机制尚不完全清楚。我们最近证明了DOX导致 线粒体(而不是整个细胞)铁积累,线粒体铁的减少导致 针对DIC的保护。然而,这些研究主要是在体外和动物模型中进行的, 目前尚不清楚线粒体铁含量较高是否会增加患者对DIC的易感性。要扩展这些功能 除了动物模型之外,我们已经建立了几个人类诱导的多能干细胞系- 来源于经历过DIC(DIC-CM)或没有DIC的患者的心肌细胞(HiPSC-CM) 暴露于DOX后的心脏毒性(NODIC-CM),并显示它们概括了患者在 在体外,他们容易受到一种特殊形式的铁介导的细胞死亡的影响,这种细胞死亡被称为铁性下垂。使用RNA- SEQ,我们还发现了DOX后DIC样本中一些线粒体铁基因的改变 治疗。最后,我们证明了DIC患者的HiPSC-CM显示线粒体铁升高 在接触了DOX之后。我们的中心假设是线粒体铁在易感性中起关键作用。 对人类的DIC,线粒体铁的减少(通过铁络合剂或通过调节 参与线粒体铁稳态的基因)改变心肌细胞对DOX的敏感性。我们也 假设DOX从亚细胞室的清除是由线粒体铁调节的 通过有丝分裂,这一过程在DIC中受损。在目标1中,我们将确定DIC-CM是否 由于线粒体铁的积累,更容易受到DOX毒性的影响,而且 线粒体铁提高了这些细胞中的细胞活力。我们将在DIC-CM中调节线粒体铁和 使用线粒体可渗透铁络合剂(包括我们实验室发现的新的螯合剂)的NODIC-CM,如下 通过接触DOX以及铁性下垂和细胞活力的评估。在目标2中,我们将确定是否 我们的RNA-SEQ分析中确定的线粒体铁相关基因的调节改变了对DOX的易感性。 我们的研究表明,ABCB7和ABCB8(介导线粒体铁的蛋白质)的mRNA水平 出口)和MFRN2(一种线粒体铁进口商)会因DOX治疗而改变。我们将删除ABCB7或 来自Nodic的HiPSC中的ABCB8(这将导致线粒体铁的增加)和来自来自Nodic的HiPSC中的MFRN2 使用CRISPR-Cas9的DIC(导致线粒体铁减少),随后产生HiPSC-CM, 暴露于DOX,并评估细胞活力。最后,在目标3中,我们将确定线粒体 铁调节DOX的清除,DOX清除的固有缺陷增加了DIC的易感性。我们 将评估DOX-CM和DIC-CM的DOX清除、线粒体动力学和有丝分裂 铁络合剂的存在和不存在,以及线粒体铁基因的调节。我们还将评估 Abcb8基因敲除和转基因小鼠心脏的DOX清除和有丝分裂

项目成果

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Hossein Ardehali其他文献

Hossein Ardehali的其他文献

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{{ truncateString('Hossein Ardehali', 18)}}的其他基金

Role of mRNA-binding protein tristetraprolin in cardiac mRNA regulation and the development of heart failure
mRNA结合蛋白tristetraprolin在心脏mRNA调节和心力衰竭发展中的作用
  • 批准号:
    10544156
  • 财政年份:
    2021
  • 资助金额:
    $ 40万
  • 项目类别:
Role of mRNA-binding protein tristetraprolin in cardiac mRNA regulation and the development of heart failure
mRNA结合蛋白tristetraprolin在心脏mRNA调节和心力衰竭发展中的作用
  • 批准号:
    10365412
  • 财政年份:
    2021
  • 资助金额:
    $ 40万
  • 项目类别:
Mechanistic insights into the role of mitochondrial iron in doxorubicin-induced cardiomyopathy using human induced pluripotent stem cells
使用人类诱导多能干细胞深入了解线粒体铁在阿霉素诱导的心肌病中的作用
  • 批准号:
    10352437
  • 财政年份:
    2020
  • 资助金额:
    $ 40万
  • 项目类别:
Mechanistic insights into the role of mitochondrial iron in doxorubicin-induced cardiomyopathy using human induced pluripotent stem cells
使用人类诱导多能干细胞深入了解线粒体铁在阿霉素诱导的心肌病中的作用
  • 批准号:
    9916208
  • 财政年份:
    2020
  • 资助金额:
    $ 40万
  • 项目类别:
Mechanistic insights into HIV-mediated heart failure with preserved ejection fraction
HIV介导的射血分数保留的心力衰竭的机制见解
  • 批准号:
    9476609
  • 财政年份:
    2018
  • 资助金额:
    $ 40万
  • 项目类别:
Third Coast HIV-Related Cardiovascular and Sleep Disorders K12 Career Development Program
第三海岸 HIV 相关心血管和睡眠障碍 K12 职业发展计划
  • 批准号:
    10216328
  • 财政年份:
    2018
  • 资助金额:
    $ 40万
  • 项目类别:
Third Coast HIV-Related Cardiovascular and Sleep Disorders K12 Career Development Program
第三海岸 HIV 相关心血管和睡眠障碍 K12 职业发展计划
  • 批准号:
    10432041
  • 财政年份:
    2018
  • 资助金额:
    $ 40万
  • 项目类别:
Third Coast HIV-Related Cardiovascular and Sleep Disorders K12 Career Development Program
第三海岸 HIV 相关心血管和睡眠障碍 K12 职业发展计划
  • 批准号:
    9761573
  • 财政年份:
    2018
  • 资助金额:
    $ 40万
  • 项目类别:
Third Coast HIV-Related Cardiovascular and Sleep Disorders K12 Career Development Program
第三海岸 HIV 相关心血管和睡眠障碍 K12 职业发展计划
  • 批准号:
    9614669
  • 财政年份:
    2018
  • 资助金额:
    $ 40万
  • 项目类别:
Northwestern University Molecular and Translational Cardiovascular Training Program
西北大学分子与转化心血管培训项目
  • 批准号:
    9358906
  • 财政年份:
    2017
  • 资助金额:
    $ 40万
  • 项目类别:

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