The role of antiviral programs in bacterial sepsis

抗病毒治疗在细菌性败血症中的作用

基本信息

批准号：
10687161
负责人：
Takashi Hato
金额：
$ 40.1万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-23 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10687161
关键词：
Acceleration Acute Renal Failure with Renal Papillary Necrosis Adenosine Animal Model Anti-Inflammatory Agents Antibodies Antisense Oligonucleotides Antiviral Response Bacteremia Bacterial Infections Binding Complex Coupled Cytoplasm Data Development Disease Double Effect Double-Stranded RNA Elements Endotoxins Eukaryotic Initiation Factors Functional disorder Genes Genetic Transcription Heart Hour Immunoprecipitation Infection Inflammation Inflammatory Injury to Kidney Inosine Intensive Care Units Interferons Kidney Kidney Failure Link Mediating Mediator Mission Mitochondria Modeling Multiple Organ Failure Mus Nature Nuclear Nucleic Acids Open Reading Frames Organ Organ failure Pathologic Pathway interactions Phase Phosphorylation Phosphotransferases Prognosis Prokaryotic Initiation Factor-2 Protein Dephosphorylation Proteins Public Health Publishing RNA RNA Binding RNA Editing Recovery Reporting Repression Research Role Sepsis Severities Site Source Sterility Stimulus Stress Supportive care Syndrome TLR3 gene TLR4 gene Therapeutic Intervention Translational Repression Translations United States National Institutes of Health Untranslated Regions Up-Regulation Viral Viral Genes Virus Diseases Work mimicry mortality novel diagnostics novel therapeutics pathogen preventive intervention programs receptor septic stress granule successful intervention targeted treatment therapeutically effective timeline tissue injury transcriptome sequencing translatome viral RNA

项目摘要

Project Summary/Abstract Sepsis is the most common cause of acute kidney injury in the intensive care unit and is coupled with very high mortality. It is a highly dynamic pathological state in which a wide array of pro- and anti-inflammatory pathways are aberrantly activated, resulting in a complex syndrome that evolves rapidly over hours. Therefore, determining the timeline of sepsis and developing timeline-specific therapies are essential for successful interventions. Recently, we examined temporal changes in the translatome of the kidney in animal models of bacterial sepsis. We showed that 1) initial outburst of inflammation is accompanied by significant increases in RNA transcription and translation, 2) the initial inflammatory phase is followed by activation of antiviral programs, and 3) the activation of antiviral programs leads to translation shutdown—a hallmark of late phase sepsis. Crucially missing from this recent work is the nature and source of the antiviral program activators in the absence of an actual viral infection. We hypothesize that induction of the initial inflammatory cascades results in a state of self-RNA overburden, which provokes a milieu resembling that of a viral infection. In this proposal, we will investigate the role of endogenous RNA stress as the determinant of antiviral program activation and resultant sepsis-induced organ failure. This work will provide an important framework for understanding the link between the early phase inflammation and late phase total organ shutdown, and could lead to novel diagnostic and therapeutic applications in sepsis-induced kidney failure.

项目概要/摘要脓毒症是重症监护病房中急性肾损伤的最常见原因，并且与非常高的这是一种高度动态的病理状态，其中存在多种促炎和抗炎途径。被异常激活，导致一种复杂的综合症，并在数小时内迅速演变。确定脓毒症的时间表并开发针对时间表的治疗方法对于成功至关重要最近，我们检查了动物模型中肾脏翻译组的时间变化。我们发现，1）炎症的最初爆发伴随着细菌性败血症的显着增加。 RNA 转录和翻译，2) 初始炎症阶段之后是抗病毒药物的激活程序，3）抗病毒程序的激活导致翻译关闭——晚期的标志这项最近的工作中最重要的是缺少了抗病毒程序激活剂的性质和来源。我们捕捉到了最初炎症级联的诱导。导致自身 RNA 负担过重的状态，从而引发病毒感染的环境重新组装。提案中，我们将研究内源性 RNA 应激作为抗病毒方案决定因素的作用这项工作将为研究提供一个重要的框架。了解早期炎症和晚期全器官关闭之间的联系，并且可以导致脓毒症引起的肾衰竭的新诊断和治疗应用。