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: 10392324
• 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/10392324
• 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; 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; Laboratories; Lead; Link; Longevity; 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; base; cardiogenesis; cardioprotection; cell type; cytosolic receptor; ds-DNA; experimental study; gain of function; guanylate; improved; in vivo Model; insight; ischemic injury; macrophage; 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CANTOS试验证明，针对白介素1β的抗炎疗法降低了 心血管事件的发生率。但是，我们缺乏限制触发炎症损伤的疗法 通过急性缺血，即使它显然与临床结局明显联系在一起。知识的关键差距 了解危险识别，尤其是细胞内危险识别，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 修改危险识别以包含感染介导的损伤。该提议的总体目的是 确定DNA及其胞质受体如何循环GAMP合酶（CGA）传播损伤。 缺血。损坏心肌富含两种线粒体（每副副本， 心肌细胞）和核DNA。当大量DNA对心肌修复构成严重威胁 巨噬细胞，专业的吞噬细胞，检测并以鲁棒的炎症反应做出反应 旨在从进化的角度摆脱病原体。该项目的中心假设是 CGA对DNA的识别通过激活I型干扰素（IFN）维持炎症巨噬细胞（IFN） 促进AIM2的途径（黑色素瘤2中不存在）炎症；结果，CGA在缺血诱导的 重塑。该假设已根据初步数据和最近发表的工作提出 申请人的实验室。拟议研究的理由是了解细胞内免疫 缺血性触发的感染具有发现限制与感染相关损伤的有效方法。 在强大的初步数据的指导下，该假设将通过追求以下特定目的来检验：1） 确定巨噬细胞中的CGA激活驱动病理重塑和HF； 2）确定 CGA介导的信号传导激活了AIM2炎症小体途径。 CGA激活1型干扰素 - 介导的信号传导控制鸟苷酸结合蛋白（GBP）的表达。 Gbps不稳定 吞噬体并导致DNA释放到细胞质和触发AIM2炎性体激活中； 3） 确定抑制CGA途径的有效方法，以减少缺血后的重塑和HF 受伤。 AIM 1将使用CGASF/F小鼠系列解决，以确定巨噬细胞为负责的细胞类型。 在第二个目标下，CGAS依赖性AIM2炎性激活和Gbps的基本作用 将使用体外和体内模型的功能实验的损失或增益进行检查。 AIM 3将测试 潜在的保护免受抑制CGAS介导的信号传导的免疫调节剂的保护，其中包括两个临床 可用代理。这项研究在概念上是通过靶向DNA及其胞质感应系统的新颖的。 传统上，在心肌缺血的环境中被视为病毒反应途径。知识获得的意志 垂直促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 疾病是巨大的伯宁，通常是我们退伍军人的毁灭性状况，拟议的研究使现场移动 通过寻找减轻烧伤和改善护理的新颖策略来向前发展。