Role of cGAS-STING in Afterload-Induced Cardiac Remodeling

项目总结 虽然很早就知道免疫反应是心脏对压力的反应的关键，但我们对 对后负荷应激反应发生的心肌重构事件是有限的。最近，我们报道了一个关键的 CGAS-STING(cGMP-AMP合成酶-干扰素基因刺激因子)在心肌梗死中的作用vbl.去，去 展望未来，我们发现了cGAS-STING在负荷诱导的心肌肥厚和衰竭中的新作用的证据。我们 令人惊讶的是，失去刺痛会加剧由压力压力引发的肥大和纤维化。 我们观察到CD86、CD80和CD28、T细胞活化的标志和细胞毒性T细胞显著增加 在刺痛不足的心脏中的增殖。此外，代表抗原提呈树突状细胞的CD103+细胞 与WT相比，刺痛不足的心脏对压力超负荷的反应增加了一倍。此外，我们的 数据显示，与cGAS相反，STING在心脏免疫细胞和成纤维细胞中表达 主要存在于巨噬细胞中。STING分布范围更广表明其在心脏疾病中的作用更为突出 肥大。基于这一证据，我们建议对STING进行研究，以剖析其潜在的分子 电路。我们假设STING调节T细胞的激活和抗原提呈，适应性免疫过程 在后负荷应激的设置下，对心肌重塑和心力衰竭的发展至关重要。 在这里，我们建议进行研究，以定义和操纵后负荷应激中T细胞功能的刺依赖调节。 诱导心脏重塑，主要表现为心肌肥厚和终末期收缩功能障碍。用一只眼睛 为了最终翻译给心脏病患者，我们还利用了药理学工具，其中一些是 目前正在癌症的临床试验中进行测试，以操纵刺痛信号。 CGAS-STING途径介导的免疫反应，跨越先天和适应性元件，代表着一种 心脏重构和衰竭的全新机制。此外，在这些研究中获得的知识是 这可能有助于阐明其他形式的心脏病，并阐明癌症免疫疗法的心脏并发症。 我们提出了一系列全面的研究来确定cGAS-sting在后负荷诱导的心脏中的作用。 改建。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。我们已经开发出 在整个计划中实现多点双向协作，共享试剂和见解以及优势 来自对核心设施的广泛使用。

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.