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MicroRNA-181b and Sepsis

MicroRNA-181b 和脓毒症

基本信息

批准号：
8944822
负责人：
Rebecca M Baron
金额：
$ 46.25万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-15 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8944822
关键词：
3&apos Untranslated Regions Adhesions Adhesives Adult Respiratory Distress Syndrome Anti-Inflammatory Agents Anti-inflammatory Binding Biological Biological Assay Biological Markers Blood Vessels Bronchoalveolar Lavage Fluid Cause of Death Cell Adhesion Cell Adhesion Molecules Cell Communication Cell physiology Cessation of life Clinical Critical Illness Data Disease E-Selectin Endothelial Cells Endotoxemia Event Experimental Models Extravasation Foundations Functional disorder Gene Targeting Generations Genetic Goals Human Importins Infection Inflammation Inflammation Mediators Inflammatory Injury Laboratories Lead Leukocytes Link Lung Mediator of activation protein MicroRNAs Modeling Molecular Mus Mutation NF-kappa B NFKB Signaling Pathway Nuclear Translocation Organ Organ failure Outcome PTGS2 gene Pathogenesis Pathway interactions Patients Permeability Phosphoric Monoester Hydrolases Phosphorylation Plasma Plasminogen Activator Inhibitor 1 Production Property Proteins Proto-Oncogene Proteins c-akt Regulation Replacement Therapy Reporter Genes Resveratrol Role Sampling Sepsis Sepsis Syndrome Septic Shock Severities Signal Transduction Small Interfering RNA Stimulus Therapeutic Thrombin Thrombosis Time Tissues Tumor Necrosis Factor-alpha Untranslated RNA Untranslated Regions Vascular Cell Adhesion Molecule-1 Vascular Diseases Vascular Endothelium Vascular Permeabilities base crosslinking and immunoprecipitation sequencing cytokine endothelial dysfunction human subject improved in vivo inflammatory marker insight intravenous administration intravital microscopy lung injury monolayer mortality novel novel therapeutic intervention overexpression protective effect public health relevance response septic small molecule therapy development transcriptome sequencing vascular inflammation

项目摘要

DESCRIPTION (provided by applicant): Accumulating studies highlight a critical role for endothelial cell (EC) inflammation and dysfunction in the pathogenesis of septic shock and sepsis-induced lung injury, leading causes of death among critically ill patients. Excessive generation of pro-inflammatory mediators can lead to collateral vascular dysfunction, an effect that confers pro-adhesive, pro-permeability, and pro-thrombotic properties to ECs. Therefore, modulating these events in the vascular endothelium may provide a novel therapeutic approach to limit the sequelae of sepsis and sepsis-induced lung injury. MicroRNAs (miRNAs) are small, non-coding RNAs that suppress the expression of target genes at the post-transcriptional level and are involved in a range of biological responses. However, the role of microRNAs in sepsis-associated endothelial dysfunction remains poorly defined. Using a microarray profiling approach in ECs, we identified that miR-181b expression is rapidly reduced in the vascular endothelium from endotoxemic mice - observations that are recapitulated in human subjects with sepsis in vivo. Our studies have uncovered that miR-181b inhibits targets that control 2 key signaling pathways, NF-kB and AKT/eNOS, that govern EC adhesion, vascular permeability, and proinflammatory mediators implicated in sepsis and sepsis-induced lung injury. Preliminary functional studies in ECs reveal that miR-181b potently inhibits effects on leukocyte adhesion, EC permeability, and thrombin-induced EC inflammation. MiR-181b suppresses the activation of the NF-kB pathway uniquely in ECs by binding to the 3'UTR of importin-a3, a protein involved in NF-kB nuclear translocation in ECs and not leukocytes. In contrast, miR-181b induces eNOS-phosphorylation by directly targeting the phosphatase PHLPP2, known to inhibit AKT-phosphorylation. Finally, treatment of mice by systemic intravenous administration of miR-181b mimics as "replacement therapy" reduces endotoxemia-induced EC inflammatory markers, leukocyte accumulation, lung injury, and markedly improves survival. Thus, we hypothesize that miR-181b may serve as a critical homeostatic regulator of ECs and vascular dysfunction in sepsis and sepsis-induced lung injury. To further understand the protective role of miR-181b in sepsis, we propose: in Aim1, to delineate the proximal events during sepsis regulating miR-181b expression. In Aim2, using inflammatory stimuli including human plasma samples from patients with sepsis and sepsis-induced lung injury, we will dissect the mechanisms by which miR-181b regulates NF-kB and AKT signaling in response to EC dysfunction. In Aim3, we will explore the effect and timing of altered miR-181b expression, or its targets (using genetic, siRNA, or pharmacological approaches to importin-a3 or PHLPP2), on experimental models of sepsis and EC function in vivo. Successful completion of the proposed studies will identify significant insights regarding miR-181b function in EC inflammation, vascular leak, and microvascular thrombosis, and may provide discrete, novel targets for sepsis-induced lung injury.