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,抗癌药)由于其心脏毒性副作用而限制了其临床应用。的 DOX诱导的心脏毒性(DIC)的机制尚未完全清楚。我们最近发现, 线粒体(与总细胞相反)铁积累,线粒体铁减少导致 保护DIC。然而,这些研究主要在体外和动物模型中进行, 目前尚不清楚线粒体铁含量是否与DIC易感性有关。扩展这些 除了动物模型的发现,我们已经建立了几个人类诱导多能干细胞系, 来自经历DIC(DIC-CM)或未经历DIC(DIC-CM)的患者的衍生心肌细胞(hiPSC-CM) 心脏毒性(noDIC-CM),并表明它们概括了患者的表型, 它们易受一种特殊形式的铁介导的细胞死亡的影响,称为“铁凋亡”。使用RNA- seq,我们还确定了DOX后DIC样本中许多线粒体铁基因发生改变 治疗最后,我们已经证明,DIC患者的hiPSC-CM显示线粒体铁升高, 在DOX暴露后。我们的中心假设是线粒体铁在易感性中起关键作用 在人类DIC中,线粒体铁的减少(无论是通过铁螯合剂还是通过调节 线粒体铁稳态相关基因)改变心肌细胞对DOX的敏感性。我们也 假设DOX从亚细胞区室的清除受线粒体铁的调节, 这一过程在DIC中受损。在目标1中,我们将确定DIC-CM是否 由于线粒体铁积累,更容易受到DOX毒性的影响, 线粒体铁改善这些细胞中的细胞活力。我们将在DIC-CM中调节线粒体铁, 使用线粒体渗透性铁螯合剂(包括我们实验室鉴定的新螯合剂)的noDIC-CM, 通过暴露于DOX并评估铁凋亡和细胞活力。在目标2中,我们将确定 在我们的RNA-seq分析中鉴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,ABCB 7和ABCB 8(介导线粒体铁的蛋白质)的mRNA水平 输出)和MFRN 2(线粒体铁输入者)被DOX处理改变。我们将删除ABCB 7或 来自noDIC的hiPSC中的ABCB 8(其将导致线粒体铁的增加)和来自noDIC的hiPSC中的MFRN 2(其将导致线粒体铁的增加)。 使用CRISPR-Cas9进行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,我们将确定线粒体是否 铁调节DOX清除,DOX清除中的固有缺陷促进DIC的易感性。我们 将评估DOX后noDIC-CM和DIC-CM中的DOX清除率、线粒体动力学和线粒体自噬, 铁螯合剂的存在和不存在,以及线粒体铁基因的调节。我们亦会评估 DOX后Abcb 8敲除和转基因小鼠模型心脏中的DOX清除和线粒体自噬。

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:
    9916208
  • 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:
    10352437
  • 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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