Function of circulating exosomes in sepsis-induced immunosuppression

循环外泌体在脓毒症诱导的免疫抑制中的功能

• 批准号: 10242614
• 负责人: Nicholas S Britt
• 金额: $ 14.55万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-15 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10242614
• 关键词: Adaptive Immune System; Affect; Anti-Inflammatory Agents; Apoptosis; Automobile Driving; Biological; Biological Assay; Biological Markers; Biological Process; Biological Response Modifiers; Cause of Death; Cell Culture Techniques; Cells; Cessation of life; Characteristics; Clinical Research; Communicable Diseases; Complex; Critical Illness; Data; Detection; Disease; Disease Pathway; Functional disorder; Future; Goals; Human; Immune; Immune System Diseases; Immune response; Immune signaling; Immunologic Markers; Immunosuppression; Immunotherapeutic agent; Infection; Inflammation; Innate Immune System; Interleukin-10; Laboratories; Letters; Life; Light; Mediating; Membrane; Messenger RNA; MicroRNAs; Microfluidics; Molecular Analysis; Mus; Neutrophil Infiltration; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmacists; Phase; Plasma; Preparation; Process; Proteins; Research; Role; Sampling; Scientist; Sepsis; Sepsis Syndrome; Septic Shock; Signal Pathway; Site; T-Lymphocyte; Technology; Testing; Time; Translational Research; assay development; base; cell type; clinical biomarkers; cytokine; cytokine release syndrome; endothelial dysfunction; exhaustion; exosome; extracellular vesicles; immune function; immunological status; microRNA biomarkers; microvesicles; monocyte; mortality; mouse model; nanoengineering; nanovesicle; neutrophil; novel; novel marker; polymicrobial sepsis; precision medicine; pressure; prevent; programs; response; sample collection; septic; septic patients; skills; therapeutic target; tool; transcriptomics; vesicular release

Sepsis syndrome consists of a dysregulated host response to infection involving a complex interplay between proinflammatory and anti-inflammatory processes. Initially, sepsis is characterized by excessive cytokine release that shifts over time to a state of immune exhaustion characterized by T cell dysfunction and apoptosis. Although most sepsis-related deaths occur during this late hypoimmune state, there are currently no reliable biomarkers to stratify immune status of patients with sepsis to guide precision delivery of immunotherapeutic agents. Exosomes are membrane-bound nanovesicles containing miRNAs which are increasingly recognized as key regulators of host immune response. Leveraging recent advances in microfluidic detection of exosomes and associated cargo, the goal of this proposal is to accurately define key immune pathways disrupted in sepsis and to identify clinically useful biomarkers of immune status. Previous research has largely focused on the role of exosomes in mediating inflammation and endothelial dysfunction characteristic of septic shock; however, preliminary data from our laboratory challenge this paradigm and demonstrate that circulating exosomes also contribute to sepsis-induced immune suppression. Based on this premise, we hypothesize that sepsis results in immune dysfunction with corresponding changes in circulating concentrations of exosomal miRNA (exo-miRNA) that can be used as biomarkers of immune status. To test these hypotheses, we will execute the following Specific Aims: i) identify circulating exo-miRNA markers of sepsis; ii) evaluate the effect of plasma-derived exosomes from septic patients on immune function; and iii) develop a nanoengineered chip-based bioanalytic platform for the quantitation of exo-miRNA markers of sepsis. The candidate is a pharmacist-scientist with a proven commitment to translational science in infectious diseases and precision medicine. Additional skills in transcriptomics and bioanalytical assay development acquired through execution of this proposal will facilitate the candidate’s establishment of a research program devoted to optimizing the management of critically ill patients with life-threatening infectious diseases.

脓毒症综合征是一种宿主对感染的反应失调，涉及以下因素之间的复杂相互作用： 促炎和抗炎过程。最初，脓毒症的特征是过度的细胞因子 释放，随时间推移转变为以T细胞功能障碍为特征的免疫衰竭状态， 凋亡虽然大多数败血症相关的死亡发生在这种晚期免疫功能低下状态，但目前 没有可靠的生物标志物来对脓毒症患者的免疫状态进行分层，以指导 免疫抑制剂。外来体是含有miRNA的膜结合纳米囊泡， 越来越多地被认为是宿主免疫反应的关键调节剂。利用最近的进展， 外泌体和相关货物的微流控检测，该提案的目标是准确定义关键 免疫途径在脓毒症中被破坏，并鉴定免疫状态的临床上有用的生物标志物。先前 研究主要集中在外泌体在介导炎症和内皮功能障碍中的作用 感染性休克的特征;然而，我们实验室的初步数据挑战了这种范式， 证明循环外泌体也有助于脓毒症诱导的免疫抑制。基于此 在此前提下，我们假设脓毒症导致免疫功能障碍，并导致循环系统发生相应的变化。 在一些实施方案中，可以使用可用作免疫状态的生物标志物的外泌体miRNA（exo-miRNA）的浓度。测试 基于这些假设，我们将执行以下具体目标：i）鉴定循环的exo-miRNA标记物， ii）评估来自脓毒症患者的血浆来源的外泌体对免疫功能的影响;和iii） 开发一种基于纳米工程芯片的生物分析平台，用于定量 败血症 候选人是一名药剂师-科学家，致力于传染病领域的转化科学。 疾病和精准医疗。转录组学和生物分析检测开发方面的额外技能 通过执行本提案获得的资金将有助于候选人建立研究计划 致力于优化对危及生命的传染病危重症患者的管理。