Long Non-Coding RNA, TLR Tolerance and Sepsis

长非编码 RNA、TLR 耐受性和脓毒症

基本信息

批准号：
9297691
负责人：
ANDREI E MEDVEDEV
金额：
$ 19.94万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9297691
关键词：
Address Affect Agonist American Anti-Inflammatory Agents Anti-inflammatory Bacteria Cells Cessation of life Clinical Trials Data Dendritic Cells Development Disease Disseminated Intravascular Coagulation Endotoxins Epithelial Cells Exhibits Failure Future Genetic Polymorphism Genetic Transcription Grant Health Human IRAK1 gene IRAK3 gene IRAK4 gene Immune Immunocompromised Host Immunoprecipitation Immunosuppression Impairment Infection Inflammation Mediators Inflammatory Intensive Care Units Interleukin-1 alpha Mass Spectrum Analysis Mediating Mediator of activation protein Mission Molecular Molecular Target Mus Myeloid Cells National Institute of Allergy and Infectious Disease Natural Immunity Organ Pathway interactions Patients Pattern Phase Phenotype Post-Transcriptional Regulation Post-Translational Protein Processing Publishing Receptor Signaling Regulation Role Secondary to Sepsis Shapes Signal Pathway Signal Transduction TLR4 gene Testing Toll-like receptors Transcript Translational Research Untranslated RNA antimicrobial cytokine design differential expression drug testing effective therapy experimental study improved knock-down macrophage microbial monocyte mortality next generation sequencing novel strategies pathogen prevent programs response secondary infection septic

项目摘要

Sepsis remains one of the major health threats in the U. S., affecting ~750,000 Americans per year, with mortality rate up to 50%. Many septic patients survive the initial “cytokine storm” but develop profound immunosuppression, become immunocompromised and succumb to secondary infections. Monocytes from such immunocompromised septic patients have “re- programmed” Toll-like receptor (TLR) 4 signaling, showing suppressed pro-inflammatory cytokines but unchanged or increased expression of anti-inflammatory and anti-microbial mediators, reminiscent of endotoxin tolerance. Long non-coding RNAs (lncRNAs) have recently emerged as new regulators of TLR signaling pathways, but how changes in lncRNAs “shape” re- programming of responses of myeloid cells during TLR tolerance and sepsis is unknown. Our preliminary and published data has identified lncRNAs in human THP1 monocytes and mouse macrophages with significant changes in expression upon TLR4 challenge and endotoxin tolerization. We showed that knock-down of PCGEM1 lncRNA in THP-1 cells and deficiencies of natural antisense transcript-IL-1α, linc-Cox2 or Eps lncRNAs in mouse macrophages significantly affect LPS signaling. We also found that Eps-/- Ms are compromised in the induction of endotoxin tolerance. These data supports our hypothesis that altered expression and functions of lncRNAs in myeloid cells promote TLR tolerance and sepsis-associated immunosuppression by reprogramming TLR responses at the level transcriptional and post-transcriptional regulation of inflammatory mediators. To test this hypothesis, we have designed the following Specific Aims: 1. Identify the impact of TLR4 tolerance and sepsis on expression of lncRNAs in myeloid cells; and 2. Determine the functional significance for lncRNAs in TLR4 signaling and tolerance. Having completed this project, we will determine the role for lncRNAs in “reprogramming” of TLR signaling in myeloid cells during development of TLR tolerance and sepsis. This project is expected to improve our understanding of the mechanisms by which lncRNAs modulate antimicrobial responses of myeloid cells, and define molecular targets of lncRNAs for future translational research in human patients with sepsis. These advances would be of key importance for improving treatment of sepsis in the U.S.

败血症仍然是美国主要的健康威胁之一，影响了约75万美国人每年，死亡率高达50％。许多化粪池患者在最初的“细胞因子风暴”中幸存下来但是发展深刻的免疫抑制，变得免疫功能低下并屈服于继发感染。这种免疫功能低下的化粪池患者的单核细胞具有“ 编程“ Toll样受体（TLR）4信号传导，显示抑制炎症性炎症细胞因子，但抗炎和抗微生物的表达不变或增加介体，让人想起内毒素的耐受性。最近的非编码RNA（LNCRNA）具有出现是TLR信号通路的新调节剂，但是LNCRNAS“形状”如何变化 TLR耐受性和败血症期间髓样细胞反应的编程是未知的。我们的初步和已发布的数据已确定人类THP1单核细胞和小鼠中的LNCRNA 巨噬细胞在TLR4挑战和内毒素耐受性上表达显着变化。我们表明，THP-1细胞中的PCGEM1 lncRNA敲低和自然反义的缺陷小鼠巨噬细胞中的转录物IL-1α，linc-cox2或EPS LNCRNA显着影响LPS信号传导。我们还发现，在诱导内毒素耐受性时，EPS - / - MS受到损害。这些数据支持我们的假设，即改变髓样细胞中LNCRNA的表达和功能促进 TLR的耐受性和与败血症相关的免疫抑制，通过对TLR反应进行重编程炎症介质的水平转录和转录后调节。测试这个假设，我们设计了以下特定目的：1。确定TLR4公差的影响和败血症在髓样细胞中的LNCRNA表达；和2。确定功能意义 TLR4信号传导和耐受性中的lncRNA。完成该项目后，我们将确定 TLR公差发展过程中TLR信号传导的“重编程”中的LNCRNA 和败血症。预计该项目将提高我们对所采用的机制的理解 LNCRNA调节髓样细胞的抗菌反应，并定义LNCRNAS的分子靶标用于脓毒症患者的未来翻译研究。这些进步将是关键在美国改善败血症治疗的重要性