Type I Interferon Responses in the Pathobiology of Anthracycline-induced Cardiotoxicity

蒽环类药物引起的心脏毒性病理生物学中的 I 型干扰素反应

• 批准号: 10984303
• 负责人: Andrew Phillip West
• 金额: $ 37.01万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-05 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10984303
• 关键词: Type; Interferon; Responses; Pathobiology; Anthracycline

Anthracycline chemotherapeutics, such as doxorubicin (Doxo), are among the most effective and widely used antineoplastic drugs, yet their clinical application is limited by the damaging cardiac side effects that occur in many patients. Anthracycline-induced cardiotoxicity (AIC) can manifest acutely during cancer treatment, but can also cause life threatening cardiomyopathy and heart failure that develops years after the cessation of chemotherapy. Despite significant effort, the underlying mechanisms responsible for AIC are not fully defined, and it remains impossible to predict which patients will experience cardiotoxicity. Thus, there is an urgent need to advance mechanistic understanding in order to discover novel treatments and/or predictive biomarkers for this devastating condition. The overall objective of this proposal is to comprehensively define how type I interferon (IFNab) signaling, a pleiotropic innate immune pathway, potentiates the cardiotoxic effects of Doxo chemotherapy. The central hypothesis is that Doxo-induced cardiac DNA damage triggers the Stimulator of Interferon Genes (STING)-dependent production of IFNab, in turn driving a self-propagating cycle of mitochondrial dysfunction, reactive oxygen species (ROS) production, and cardiomyocyte death that contributes to cardiac remodeling and failure. In support of this hypothesis, ongoing studies have revealed that Doxo robustly engages STING to upregulate IFNab responses in cardiac cells and tissue. Strikingly, both male and female mice lacking STING or IFNab signaling are protected from Doxo-induced cardiac mitochondrial damage, myocardial remodeling, and left ventricle dysfunction. Conversely, treating melanoma-bearing mice with adjuvant IFNa in addition to Doxo results in enhanced cardiac fibrosis and contractility defects relative to tumor-bearing mice receiving Doxo alone. To gain additional insight into what appears to be an unappreciated yet fundamental driver of AIC, three related, but independent, aims are proposed. Aim 1 will employ single-cell approaches, a novel IFNab reporter mouse, and conditional knockout lines to define the kinetics of IFNab production in the heart and determine that STING-IFNab signaling in cardiac myeloid and myocyte populations contributes to AIC. Aim 2 will test the hypothesis that STING-IFNab signaling amplifies the cardiotoxicity of anthracyclines by potentiating mitochondrial dysfunction, iron overload, and oxidative stress. Finally, Aim 3 will establish that the IFNab-mediated upregulation of Z-DNA binding protein 1 (ZBP1) enhances sensing of cardiac DNA damage and promotes cardiac necroptosis to sustain inflammatory responses during and after Doxo chemotherapy. This proposal is innovative because it expands the current paradigms of AIC and defines the IFNab-mitochondrial nexus as a fundamental pathway contributing to myocardial damage. In addition, this research will contribute significant new information on how cardiac innate immune responses potentiate heart failure. In the long term, this work may positively impact human health by establishing IFNab as a predictive biomarker for cardiotoxicity and/or revealing novel therapeutic approaches to combat cancer therapy-related cardiac dysfunction.

蒽环类化疗药物，如阿霉素 (Doxo)，是最有效且使用最广泛的药物之一 抗肿瘤药物，但其临床应用受到以下情况的破坏性心脏副作用的限制： 很多病人。蒽环类药物引起的心脏毒性 (AIC) 在癌症治疗期间可能会急性表现，但也可能 还会导致在停止治疗数年后出现危及生命的心肌病和心力衰竭 化疗。尽管付出了巨大的努力，但导致 AIC 的底层机制尚未完全定义， 而且仍然无法预测哪些患者会出现心脏毒性。因此，迫切需要 促进机制理解，以便发现新的治疗方法和/或预测生物标志物 毁灭性的状况。该提案的总体目标是全面定义 I 型干扰素如何 (IFNab) 信号是一种多效性先天免疫途径，可增强 Doxo 的心脏毒性作用 化疗。核心假设是 Doxo 引起的心脏 DNA 损伤会触发 干扰素基因 (STING) 依赖性 IFNab 的产生，进而驱动 IFNab 的自我繁殖循环 线粒体功能障碍、活性氧 (ROS) 产生和心肌细胞死亡 导致心脏重塑和衰竭。为了支持这一假设，正在进行的研究表明，Doxo 强有力地 利用 STING 上调心脏细胞和组织中的 IFNab 反应。引人注目的是，无论是男性还是女性 缺乏 STING 或 IFNab 信号传导的小鼠可以免受 Doxo 诱导的心脏线粒体损伤， 心肌重构和左心室功能障碍。相反，用佐剂治疗携带黑色素瘤的小鼠 与荷瘤相比，IFNa 和 Doxo 会导致心脏纤维化和收缩性缺陷增强 单独接受 Doxo 的小鼠。为了获得对看似未被重视但基本的东西的更多见解 AIC 的驱动因素，提出了三个相关但独立的目标。目标 1 将采用单细胞方法， 新型 IFNab 报告小鼠，以及用于定义 IFNab 产生动力学的条件敲除系 心脏并确定心脏骨髓和肌细胞群中的 STING-IFNab 信号传导有助于 AIC。 目标 2 将检验以下假设：STING-IFNab 信号通过以下方式放大蒽环类药物的心脏毒性： 加剧线粒体功能障碍、铁超载和氧化应激。最后，目标 3 将确定 IFNab 介导的 Z-DNA 结合蛋白 1 (ZBP1) 上调增强了对心脏 DNA 损伤的感知 在 Doxo 化疗期间和之后促进心脏坏死性凋亡以维持炎症反应。这 该提案具有创新性，因为它扩展了 AIC 的当前范式并定义了 IFNab 线粒体 关系作为导致心肌损伤的基本途径。此外，这项研究将有助于 关于心脏先天免疫反应如何加剧心力衰竭的重要新信息。从长远来看， 这项工作可能通过将 IFNab 确立为心脏毒性的预测生物标志物来对人类健康产生积极影响 和/或揭示对抗癌症治疗相关的心脏功能障碍的新治疗方法。

项目成果

Label-free spatially maintained measurements of metabolic phenotypes in cells.

• DOI: 10.3389/fbioe.2023.1293268
• 发表时间: 2023
• 期刊: Frontiers in bioengineering and biotechnology
• 影响因子: 5.7

The molecular basis of tight nuclear tethering and inactivation of cGAS.

• DOI: 10.1038/s41586-020-2749-z
• 发表时间: 2020-11
• 期刊: Nature
• 影响因子: 64.8
• 作者: Zhao B;Xu P;Rowlett CM;Jing T;Shinde O;Lei Y;West AP;Liu WR;Li P
• 通讯作者: Li P

Loss of Mitochondrial Protease CLPP Activates Type I IFN Responses through the Mitochondrial DNA-cGAS-STING Signaling Axis.

• DOI: 10.4049/jimmunol.2001016
• 发表时间: 2021-04-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Torres-Odio S;Lei Y;Gispert S;Maletzko A;Key J;Menissy SS;Wittig I;Auburger G;West AP
• 通讯作者: West AP

Late-life dietary folate restriction reduces biosynthetic processes without compromising healthspan in mice.

晚年膳食叶酸限制会减少生物合成过程，而不影响小鼠的健康寿命。

• DOI: 10.1101/2024.01.12.575290
• 发表时间: 2024
• 期刊: bioRxiv : the preprint server for biology
• 作者: Blank,HeidiM;Hammer,StaciE;Boatright,Laurel;Roberts,Courtney;Heyden,KatarinaE;Nagarajan,Aravindh;Tsuchiya,Mitsuhiro;Brun,Marcel;Johnson,CharlesD;Stover,PatrickJ;Sitcheran,Raquel;Kennedy,BrianK;Adams,LGarry;Kaeberlein,Matt
• 通讯作者: Kaeberlein,Matt

Increased presence of nuclear DNAJA3 and upregulation of cytosolic STAT1 and of nucleic acid sensors trigger innate immunity in the ClpP-null mouse.

• DOI: 10.1007/s10048-021-00657-2
• 发表时间: 2021-10
• 期刊: Neurogenetics
• 影响因子: 2.2
• 作者: Maletzko A;Key J;Wittig I;Gispert S;Koepf G;Canet-Pons J;Torres-Odio S;West AP;Auburger G
• 通讯作者: Auburger G