Intracellular immunity, cytosolic DNA sensing by cyclic GAMP synthase, and macrophages in ischemic injury and cardiac remodeling

细胞内免疫、环 GAMP 合酶检测胞质 DNA 以及缺血性损伤和心脏重塑中的巨噬细胞

• 批准号: 10618801
• 负责人: Dian Cao
• 金额: --
• 依托单位: VA NORTH TEXAS HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618801
• 关键词: AIM2 gene; Acute; Address; Affect; Award; Behavior; Binding Proteins; Biology; Bone Marrow Cells; CASP1 gene; Cardiac; Cardiac Myocytes; Cardiovascular system; Caring; Cells; Chronic Phase; Clinical; Cytosol; DNA; DNA receptor; Data; Development; Disease; Drug usage; Effectiveness; Engineering; Event; Fibroblasts; Goals; Heart failure; IL18 gene; Immune; Immune response; Immunity; Immunologics; Immunology; Immunomodulators; In Vitro; Incidence; Infarction; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Injury; Interferon Type I; Interferon-beta; Interferons; Interleukin-1 beta; Intervention; Ischemia; Knock-out; Knowledge; Knowledge acquisition; Laboratories; Link; Longevity; Macrophage; Mediating; Mitochondria; Modeling; Mus; Muscle Cells; Myelogenous; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Nature; Nuclear; Oligonucleotides; Outcome; Pathologic; Pathway interactions; Patients; Periodicity; Phagocytes; Phagosomes; Pharmaceutical Preparations; Phosphotransferases; Play; Process; Production; Publishing; Quinacrine; Records; Reporter; Reporting; Research; Resources; Role; Safety; Signal Transduction; Sterility; System; TBK1 gene; Testing; Time; Translating; United States National Institutes of Health; Vacuole; Veterans; Viral; Work; amlexanox; cardioprotection; cell type; cytosolic receptor; ds-DNA; experimental study; gain of function; guanylate; improved; in vivo Model; insight; ischemic injury; mortality; myocardial damage; new therapeutic target; novel; novel strategies; novel therapeutics; overexpression; pathogen; prevent; recruit; repaired; response; sensor; targeted treatment; therapeutic target; tissue injury; tissue repair; translational impact

PROJECT SUMMARY/ABSTRACT The recent CANTOS Trial has proved that anti-infammation therapy targeting the interleukin-1β lowers the incidence of cardiovascular events. However, we lack therapies that can limit the inflammatory injury triggered by acute ischemia, even though it clearly links to worse clinical outcomes. A critical gap of knowledge in understanding danger recognition, especially intracellular danger recognition, plays a significant role, because detecting danger dictates the scope of inflammation. Our long-term goal is to develop immune modulators that modify danger recognition to contain inflammation-mediated injury. The overall objective of this proposal is to determine how DNA and its cytosolic receptor the cyclic GAMP synthase (cGAS) propagate injury triggered by ischemia. The damaged myocardium is enriched with both mitochondrial (thousands of copies per cardiomyocyte) and nuclear DNA. The large amount of DNA poses a serious threat to myocardial repair when macrophages, the professional phagocytes, detect it and respond with the robust inflammatory responses intended to get rid of pathogens from the evolutionary standpoint. The central hypothesis of this project is that recognition of DNA by cGAS sustains the inflammatory macrophages via activation of the type I interferon (IFN) pathway that promotes AIM2 (absent in melanoma 2) inflammasone; as a result, cGAS is crucial in ischemia-induced remodeling. This hypothesis has been formulated on the preliminary data and the recently published work from the applicants’ laboratory. The rationale for the proposed research is that understanding the intracellular immunity in ischemic-triggered inflammation has the potential to discover effective ways of limiting inflammation-related injury. Guided by strong preliminary data, this hypothesis will be tested by pursuing the following specific aims: 1) Determine that cGAS activation in macrophages drives pathological remodeling and HF; 2) Determine that cGAS-mediated signaling activates the AIM2 inflammasome pathway. cGAS activates type 1 interferon- mediated signaling that governs the expression of the guanylate binding proteins (GBPs). GBPs destabilize the phagosome and cause the release of DNA into the cytosol and triggers AIM2 inflammasome activation; 3) Identify effective approaches for inhibition of the cGAS pathway to reduce remodeling and HF after ischemic injury. Aim 1 will be addressed using a cGASf/f mouse line to determine macrophage as the responsible cell type. Under the second aim, the cGAS-dependent AIM2 inflammasone activation and the essential roles of GBPs will be examined using loss or gain of function experiments with in vitro and in vivo models. Aim 3 will test potential protection from immune modulators that inhibit the cGAS-mediated signaling, including two clinically available agents. The study is conceptually novel by targeting DNA and its cytosolic sensing system, traditionally viewed as a viral response pathway, in the setting of myocardial ischemia. Knowledge acquired will vertically advance our understanding of the critical role of intracellular immunity in ischemic injury. As ischemic heart disease is an enormous burden and often a devastating condition to our veterans, the proposed study moves the field forward by finding novel strategies alleviating the burden and improve care.

项目摘要/摘要 最近的CATOS试验证明，以白细胞介素1β为靶点的反感染疗法降低了 心血管事件的发生率。然而，我们缺乏可以限制引发的炎性损伤的治疗方法。 由于急性缺血，尽管它明显与更糟糕的临床结果有关。……的严重知识缺口 理解危险识别，特别是细胞内的危险识别，起着重要作用，因为 检测危险决定了炎症的范围。我们的长期目标是开发免疫调节剂， 修改危险识别以遏制炎症介导的损伤。这项提议的总体目标是 确定DNA及其胞质受体环磷酸腺苷合成酶(CGAS)如何传播由 缺血症。受损的心肌富含线粒体(每个数千个拷贝 心肌细胞)和核DNA。大量的DNA对心肌修复构成严重威胁 巨噬细胞是专业的吞噬细胞，检测到它并以强烈的炎症反应做出反应 旨在从进化的角度消除病原体。这个项目的中心假设是 CGAS对DNA的识别通过激活I型干扰素支持炎性巨噬细胞 促进AIM2(在黑色素瘤2中缺失)炎症的途径；因此，cGAS在缺血诱导中起关键作用 改建。这一假设是基于初步数据和最近发表的来自 申请人的实验室。这项拟议研究的基本原理是，理解细胞内免疫在 缺血引发的炎症有可能发现限制炎症相关损伤的有效方法。 在强劲的初步数据指导下，这一假说将通过追求以下具体目标来检验：1) 确定巨噬细胞中cGAS的激活驱动病理重塑和心衰；2)确定 CGAS介导的信号激活了AIM2炎症体途径。CGAS激活1型干扰素- 介导的信号调节鸟氨酸结合蛋白(GBP)的表达。Gbps不稳定 吞噬小体，导致DNA释放到胞浆中，触发AIM2炎性小体激活；3) 寻找抑制cGAS途径以减少缺血后重塑和心力衰竭的有效途径 受伤。目标1将使用cGASf/f小鼠系来确定巨噬细胞是负责的细胞类型。 在第二个目标下，依赖cGAS的AIM2炎症因子的激活和GBP的重要作用 将通过体外和体内模型的功能丧失或获得实验来检验。AIM 3将测试 抑制cGAS介导的信号转导的免疫调节剂的潜在保护作用，包括临床上的两种 可用代理。这项研究在概念上是新颖的，通过靶向DNA及其胞浆传感系统， 传统上被视为一种病毒反应途径，在心肌缺血的背景下。所获得的知识将 垂直推进我们对细胞内免疫在缺血性损伤中的关键作用的理解。作为缺血性心脏 疾病对我们的退伍军人来说是一个巨大的负担，而且往往是毁灭性的疾病，这项拟议的研究推动了这一领域 通过寻找新的战略来减轻负担和改善护理。