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

蒽环类化疗药物，如多柔比星（Doxo），是最有效和广泛使用的药物之一 药物，但它们的临床应用是有限的损害心脏的副作用，发生在 很多病人。蒽环类药物诱导的心脏毒性（AIC）可在癌症治疗期间急性表现，但可 也会导致危及生命的心肌病和心力衰竭，这些疾病在停止服用后数年发生。 化疗尽管作出了重大努力，但对AIC负责的基本机制尚未完全界定， 并且仍然不可能预测哪些患者将经历心脏毒性。因此，迫切需要 推进机制的理解，以发现新的治疗方法和/或预测生物标志物， 具有破坏性的病症该提案的总体目标是全面定义I型干扰素如何 （IFNab）信号传导，一种多效性先天免疫途径，增强Doxo的心脏毒性作用 化疗核心假设是Doxo诱导的心脏DNA损伤触发了 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， 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 使STING参与上调心脏细胞和组织中的IFNab应答。引人注目的是，无论是男性还是女性 缺乏STING或IFNab信号传导的小鼠被保护免受Doxo诱导的心脏线粒体损伤， 心肌重塑和左心室功能障碍。相反，用佐剂治疗荷黑色素瘤小鼠， 与荷瘤小鼠相比，IFN α与Doxo联合使用可导致心脏纤维化和收缩性缺陷增强。 单独接受Doxo的小鼠。为了获得更多的洞察力，似乎是一个不受重视的，但基本的 AIC的驱动程序，三个相关的，但独立的，提出了目标。目标1将采用单细胞方法， 新的IFNab报告小鼠和条件性敲除系，以确定IFNab产生的动力学， 心脏和确定心脏骨髓和肌细胞群中STING-IFNab信号传导对AIC有贡献。 目的2将检验STING-IFNab信号传导通过以下方式放大蒽环类药物的心脏毒性的假设： 增强线粒体功能障碍、铁过载和氧化应激。最后，目标3将确定， IFNab介导的Z-DNA结合蛋白1（ZBP 1）上调增强了心脏DNA损伤的感知， 促进心脏坏死性凋亡，以维持Doxo化疗期间和之后的炎症反应。这 该提案是创新的，因为它扩展了目前的AIC范式，并定义了IFNab-线粒体 nexus是导致心肌损伤的基本途径。此外，这项研究将有助于 心脏先天免疫反应如何增强心力衰竭的重要新信息。从长远来看， 这项工作可能会积极影响人类健康，建立IFNab作为预测生物标志物的心脏毒性 和/或揭示对抗癌症治疗相关的心功能障碍的新的治疗方法。

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.