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Role of miRNA-TLR7 signaling in platelet activation and dysfunction in sepsis

miRNA-TLR7 信号传导在脓毒症血小板激活和功能障碍中的作用

基本信息

批准号：
10242849
负责人：
Brittney Williams
金额：
$ 15.52万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
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：
2020-09-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10242849
关键词：
Adhesions Binding Blood Circulation Blood Coagulation Disorders Blood Platelets Blood coagulation Cells Clinical Coagulation Process Complication Consumption Critical Illness Data Disease Elements Family Fibrinogen Functional disorder Generations Goals HIV Hemostatic Agents Immune Immune response Immunologic Receptors In Vitro Infection Inflammation Innate Immune Response Interleukin-1 beta Intravascular Thrombus Formation Invaded Knockout Mice Leukocytes Ligands Link Literature Mediator of activation protein MicroRNAs Modeling Molecular Mus Organ failure Pathogenesis Pattern Pattern recognition receptor Pharmacology Pilot Projects Plasma Platelet Activation Platelet Count measurement Platelet aggregation Play Prevention Production Proteins RNA Role Sepsis Serotonin Severities Signal Transduction TLR7 gene Testing Thrombin Thrombocytopenia Thromboplastin Thrombus Time Toll-like receptor 11 Toll-like receptors Treatment Efficacy Wild Type Mouse base cecal ligation puncture cell injury cytokine extracellular vesicles improved in vivo insight loss of function mortality mouse model new therapeutic target novel organ injury pathogen platelet function platelet preservation receptor response sensor septic systemic inflammatory response therapeutic evaluation therapeutic target vascular inflammation

项目摘要

Project Summary Sepsis is a critical clinical condition that is caused by dysregulated host immune response to infection and characterized by organ failure and high mortality. Sepsis is associated with marked inflammation and hemostatic activation that often leads to widespread microvascular thrombus formation and global clotting dysfunction, a complication termed sepsis-induced coagulopathy (SIC). Toll-like receptors (TLRs) are innate immune receptors that respond to pathogen (PAMPs) or host-derived danger molecules (DAMPs) and drive profound inflammation. We have established a murine model of SIC characterized by time-dependent thrombocytopenia, procoagulant consumption, and global clotting dysfunction, and identified a critical role for TLR7 (a receptor for single-stranded RNAs, e.g., HIV RNA or microRNA) in the pathogenesis of SIC including thrombocytopenia, procoagulant (e.g., tissue factor, TF) production, and global clotting dysfunction. Moreover, we have observed increased circulating plasma miRNAs (e.g., miR-146a-5p) and extracellular vesicles (EVs, miRNA carrier) in sepsis, and a close correlation between the plasma RNA levels and sepsis severity. Both miR-146a-5p and septic plasma EVs induce proinflammatory and procoagulant response via a TLR7-dependent manner. Based on these data and the literature, we hypothesize that miRNA→TLR7 signaling plays an important role in regulating platelet activity and contributes to platelet dysfunction in SIC. To test this hypothesis, we propose the following three Specific Aims. In Aim 1, we will test the function and mechanisms of miRNA-TLR7 signaling in platelet activation. In Aim 2, we will determine the effect of EVs loaded with miR-146a-5p and septic plasma EVs on platelet activation and function. In Aim 3, we will investigate the role of TLR7 signaling in platelet activation and dysfunction in SIC. Completion of the proposed studies will provide new insight into the role and mechanism of miRNA-TLR7 signaling in regulating platelet activity and dysfunction in SIC, and potentially offer a novel therapeutic target.

项目概要脓毒症是一种严重的临床病症，是由宿主对感染和免疫反应失调引起的其特点是器官衰竭和高死亡率。脓毒症与明显的炎症有关止血激活通常导致广泛的微血管血栓形成和整体凝血功能障碍，一种称为败血症诱发的凝血病（SIC）的并发症。 Toll 样受体 (TLR) 是与生俱来的对病原体 (PAMP) 或宿主衍生的危险分子 (DAMP) 做出反应并驱动的免疫受体严重的炎症。我们建立了 SIC 小鼠模型，其特征是时间依赖性血小板减少症、促凝剂消耗和整体凝血功能障碍，并确定了其中的关键作用 TLR7（单链 RNA 的受体，例如 HIV RNA 或 microRNA）在 SIC 发病机制中的作用包括血小板减少症、促凝血剂（例如组织因子、TF）产生和整体凝血功能障碍。此外，我们观察到循环血浆 miRNA（例如 miR-146a-5p）和脓毒症中的细胞外囊泡（EV、miRNA 载体）与血浆 RNA 之间存在密切相关性水平和脓毒症严重程度。 miR-146a-5p 和脓毒症血浆 EV 均诱导促炎和通过 TLR7 依赖性方式产生促凝血反应。根据这些数据和文献，我们假设 miRNA→TLR7 信号在调节血小板活性中发挥重要作用，并有助于 SIC 中血小板功能障碍。为了检验这一假设，我们提出以下三个具体目标。瞄准 1，我们将测试miRNA-TLR7信号在血小板激活中的功能和机制。在目标 2 中，我们将确定装载 miR-146a-5p 的 EV 和脓毒血浆 EV 对血小板活化的影响功能。在目标 3 中，我们将研究 TLR7 信号传导在 SIC 血小板激活和功能障碍中的作用。拟议研究的完成将为 miRNA-TLR7 的作用和机制提供新的见解调节 SIC 中血小板活性和功能障碍的信号传导，并可能提供新的治疗靶点。