Role of cGAS-STING in Afterload-Induced Cardiac Remodeling

项目摘要 尽管人们早就知道免疫反应是心脏对压力反应的关键，但我们对免疫反应的理解是， 这些事件在心肌重塑中发生响应于后负荷应激是有限的。最近，我们报道了一个关键的 cGAS-STING（环GMP-AMP合成酶-干扰素基因刺激因子）在心肌梗死中的作用。去 向前，我们发现了cGAS-STING在负荷诱导的心脏肥大和衰竭中的新作用的证据。我们 他们发现STING的缺失--令人惊讶地--加剧了压力应激引发的肥大和纤维化。 我们观察到CD 86、CD 80和CD 28（T细胞活化的标志）和细胞毒性T细胞（CTL）的显著增加。 STING缺陷心脏的增殖。此外，代表抗原呈递树突细胞的CD 103+细胞 与WT相比，STING缺陷心脏中的压力超负荷反应加倍。而且我们的 数据显示，STING在心脏免疫细胞和成纤维细胞中表达，与存在的cGAS相反， 主要是在巨噬细胞中。STING更广泛的分布范围表明，STING在心血管疾病中的作用更突出。 肥厚基于这一证据，我们提出了研究重点放在STING剖析潜在的分子， 电路我们假设STING调节T细胞活化和抗原呈递，适应性免疫过程， 在后负荷应激的情况下，对心肌重塑和心力衰竭的发展至关重要。 在这里，我们提出了定义和操纵STING依赖性调节T细胞功能的研究，在后负荷应激- 诱导心脏重塑，重点是心室肥大和最终收缩功能障碍。着眼于 为了最终转化为心脏病患者，我们还利用药理学工具，其中一些是 目前正在癌症的临床试验中进行测试，以操纵STING信号。 cGAS-STING途径介导的免疫应答，跨越先天和适应性元件，代表了免疫应答的一个重要特征。 心脏重塑和衰竭的全新机制。此外，在这些研究中获得的知识是 可能揭示其他形式的心脏病，并阐明癌症免疫治疗的心脏并发症。 我们提出了一个全面的系列研究，以确定cGAS-STING在后负荷诱导的心脏 重塑这些研究在许多方面与其他3个项目中提出的工作交织在一起。我们已经开发 在整个计划中进行多点双向协作，共享试剂和见解，以及受益 大量使用核心设施

PROJECT SUMMARY Whereas it is long known that immune responses are pivotal to the heart’s reaction to stress, our understanding of those events in myocardial remodeling occurring in response to afterload stress is limited. Recently, we reported a pivotal role for cGAS-STING (cyclic GMP-AMP Synthase-Stimulator of Interferon Genes) in myocardial infarction. Going forward, we uncovered evidence for a novel role of cGAS-STING in load-induced cardiac hypertrophy and failure. We have discovered that loss of STING – surprisingly – exacerbated hypertrophy and fibrosis triggered by pressure stress. We observed a marked increase in CD86, CD80, and CD28, signatures of T cell activation, and cytotoxic T cell proliferation in STING-deficient hearts. In addition, CD103+ cells, representing the antigen presenting dendritic cell population, are doubled in response to pressure overload in STING-deficient heart compared to WT. Furthermore, our data reveal that STING is expressed in cardiac immune cells and fibroblasts, in contrast to cGAS, which is present predominantly in macrophages. STING’s broader scope of distribution suggests a more prominent role in cardiac hypertrophy. Based on this evidence, we propose studies focusing on STING to dissect the underlying molecular circuitry. We hypothesize that STING regulates T cell activation and antigen presentation, adaptive immune processes crucial to myocardial remodeling and development of heart failure, in the setting of afterload stress. Here, we propose studies to define and manipulate STING-dependent regulation of T cell function in afterload stress- induced cardiac remodeling, focusing on both ventricular hypertrophy and ultimate contractile dysfunction. With an eye toward ultimate translation to patients with heart disease, we also capitalize on pharmacological tools, some of which are currently being tested in clinical trials in cancer, to manipulate STING signaling. The cGAS-STING pathway-mediated immune response, spanning both innate and adaptive elements, represents an entirely novel mechanism of cardiac remodeling and failure. Furthermore, knowledge acquired during these studies is likely to shed light on other forms of heart disease and elucidate cardiac complications of cancer immunotherapy. We propose a comprehensive series of studies to define the role of cGAS-STING in afterload-induced cardiac remodeling. These studies interlace at many points with work proposed in the 3 other Projects. We have developed multiple points of bidirectional collaboration across the entire Program, sharing of reagents and insights, as well as benefit from extensive use of the Core facilities.