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：
10121094
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/10121094
关键词：
Acute Renal Failure with Renal Papillary Necrosis Adenosine Animal Model Anti-Inflammatory Agents Antibodies Antisense Oligonucleotides Antiviral Agents Antiviral Response Bacterial Infections Bacterial Model Binding Complex Coupled Data Development Disease Double Effect Double-Stranded RNA Elements Endotoxins Eukaryotic Initiation Factors Failure Functional disorder Genes Genetic Transcription Heart Hour Immunoprecipitation Infection Inflammation Inflammatory Injury to Kidney Inosine Intensive Care Units Interferons Kidney Kidney Failure Lead Link Mediating Mediator of activation protein Mission Mitochondria Modeling Mus Nature Nuclear Nucleic Acids Open Reading Frames Organ Organ failure Pathologic Pathway interactions Phase Phosphorylation Phosphotransferases Preventive Intervention Prokaryotic Initiation Factor-2 Proteins Public Health Publishing RNA RNA Binding RNA Editing Recovery Reporting Research Role Sepsis Severities Site Source Sterility Stimulus Stress Supportive care Syndrome TLR3 gene TLR4 gene Therapeutic Intervention TimeLine Translations Treatment Efficacy United States National Institutes of Health Untranslated Regions Up-Regulation Viral Virus Diseases Work mimicry mortality novel diagnostics novel therapeutics outcome forecast pathogen programs receptor septic stress granule successful intervention targeted treatment 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.

项目摘要/摘要败血症是重症监护病房中急性肾脏损伤的最常见原因，并与很高死亡。这是一种高度动态的病理状态，在该状态下，多种促和抗炎途径被异常激活，导致复杂的综合征在数小时内迅速发展。所以，确定败血症的时间表和开发时间表特定的疗法对于成功至关重要干预措施。最近，我们检查了动物模型中肾脏翻译体的临时变化细菌败血症。我们表明1）炎症的初始爆发是通过显着增加而实现的 RNA转录和翻译，2）初始炎症阶段随后激活抗病毒程序，以及3）抗病毒程序的激活导致翻译关闭 - 后期的标志败血症。最近的这项工作至关重要的是抗病毒程序激活剂的性质和来源没有实际的病毒感染。我们假设诱导初始炎症级联产生一种自我rna覆盖层的状态，这激发了类似于病毒感染的环境。在这个提案，我们将研究内源性RNA应力作为抗病毒程序的作用激活和由此产生的败血症诱导的器官衰竭。这项工作将为了解早期注射与晚期总器官关闭之间的联系，并且可以导致新颖的诊断和治疗应用在败血症引起的肾衰竭中。