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

蒽环类化疗药物，如阿霉素(Doxo)，是最有效和最广泛使用的药物之一 抗肿瘤药物，然而它们的临床应用受到发生在 很多病人。蒽环类药物引起的心脏毒性(AIC)可以在癌症治疗过程中急性表现出来，但也可以 也会导致危及生命的心肌病和心力衰竭，在停药数年后发生 化疗。尽管作出了巨大努力，但对AIC负有责任的基本机制尚未得到充分界定， 而且还不可能预测哪些患者会经历心脏毒性。因此，迫切需要 为了发现新的治疗方法和/或可预测的生物标记物，促进对机制的理解 毁灭性的状况。这项提案的总体目标是全面定义I型干扰素如何 (IFNab)信号转导是一种多效性的天然免疫途径，可增强多索昔布的心脏毒性效应 化疗。中心假说是Doxo诱导的心脏DNA损伤触发Stimator 干扰素基因(STING)依赖的IFNab的产生，进而驱动一个自我传播的循环 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强有力地 使STING在心肌细胞和组织中上调IFNab反应。令人惊讶的是，无论是男性还是女性 缺乏STING或IFNab信号的小鼠可免受Doxo诱导的心肌线粒体损伤， 心肌重塑和左心功能不全。相反，用佐剂治疗黑色素瘤小鼠 IFNA和Doxo联合应用可导致与荷瘤相关的心肌纤维化和收缩功能缺陷的增强 小鼠单独服用DOXO。以获得对看似未被欣赏但又基本的东西的更多洞察 AIC的驱动因素，提出了三个既相互联系又相互独立的目标。目标1将采用单细胞方法， 新的IFNab报告鼠和条件基因敲除线来定义IFNab在小鼠体内的生产动力学 并确定心肌髓系和心肌细胞群中的STING-IFNab信号在AIC中起作用。 目的2将验证这样的假设，即STING-IFNab信号通过以下方式放大了蒽环类药物的心脏毒性 加重线粒体功能障碍、铁超载和氧化应激。最后，目标3将确立 IFNab介导的Z-DNA结合蛋白1(ZBP1)上调增强了对心肌DNA损伤的感知和 促进心脏坏死性下垂，以维持多索化疗期间和之后的炎症反应。这 该方案具有创新性，因为它扩展了AIC的现有范式，并定义了IFNab-线粒体 Nexus是导致心肌损伤的基本途径。此外，这项研究还将有助于 关于心脏先天免疫反应如何加强心力衰竭的重要新信息。从长远来看， 通过将IFNab建立为心脏毒性的预测生物标志物，这项工作可能会对人类健康产生积极影响 和/或揭示对抗癌症治疗相关心脏功能障碍的新治疗方法。

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.