Role of extraceullar vesicles in directing immunometabolic homeostasis after burn injury

细胞外囊泡在烧伤后指导免疫代谢稳态中的作用

• 批准号: 10337838
• 负责人: Bruce A Cairns
• 金额: $ 1.74万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-15 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10337838
• 关键词: American; Animal Model; Anti-Inflammatory Agents; Antigen-Antibody Complex; Automobile Driving; Bacteremia; Bacterial Infections; Binding; Biological Response Modifiers; Burn Centers; Burn injury; Cells; Cessation of life; Clinical; Cytokine Signaling; Data; Development; Development Plans; Endothelial Cells; Ensure; Enzymes; Epithelial; Epithelial Cells; Experimental Designs; FRAP1 gene; Glycolysis; Goals; Graft Rejection; Grant; Homeostasis; Human; Immune; Immune System Diseases; Immune response; Immune signaling; Immunomodulators; Immunosuppression; Infection; Inflammation; Inflammatory; Inflammatory Response; Inhalation; Injury; Interleukin-10; Investigation; Lead; Leukocytes; Lung; Mediating; Metabolic; MicroRNAs; Molecular; Morbidity - disease rate; Mus; National Institute of General Medical Sciences; Opportunistic Infections; Outcome; PPAR gamma; Parents; Pathology; Pathway interactions; Patient-Focused Outcomes; Patients; Pattern; Pattern recognition receptor; Phase; Phenotype; Plasma; Play; Pneumonia; Population; Pre-Clinical Model; Predisposition; Receptor Signaling; Research; Research Training; Role; Sampling; Sepsis; Signal Transduction; Stimulus; Testing; Tissues; Toll-like receptors; Training; Trauma; United States; Vesicle; arginase; burn model; career; career development; cytokine; experience; extracellular; extracellular vesicles; high risk; immune activation; immune function; improved; indexing; innate immune function; lung injury; macrophage; microvesicles; mortality; neutrophil; novel; parent grant; pre-doctoral; preclinical study; prognostic value; receptor expression; recruit; repository; response; severe burns; systemic inflammatory response

ABSTRACT The research and training plan put forth in this Diversity Supplement will build upon key findings generated under the parent application by the pre-doctoral candidate (Micah LaTrell Willis). This Research Plan and the Training Plan submitted will provide Mr. Willis with opportunities to not only build an intellectual and technical toolbox to propel him towards the next phase of his trainee/development but provide him the career development opportunities to ensure he obtains his short and long-term career goals. Thus, support from this this Diversity Supplement will empower Mr. Willis to own and drive his research, training, and career development plans. Severe burn injury is one of the most devastating forms of trauma, with mortality rates reaching up to 12% even in specialized burn centers. Combined inhalation injury further increases this mortality rate. The primary cause of mortality are opportunistic infections which occur days to weeks after the injury, often resulting in lethal pneumonias and/or sepsis from bacteremia. Burn-induced immune dysfunction underlies this prolonged susceptibility to infection. It is known that response to bacterial infections is induced and regulated by Toll-like Receptor (TLR) and associated MyD88 signaling, causing release of key inflammatory cytokines. With our parent NIGMS grant “Damage-Induced Activation of the TLR/mTOR/PPARg Axis Regulates the Immune Response After Burn and Inhalation Injury” (R01GM131124), we are currently investigating in human and pre-clinical studies that immune dysfunction after burn and inhalation injury involves aberrant MyD88-mediated TLR signaling by damage associated molecular pattern molecules (DAMPs) released after injury. This results in aberrant cytokine signaling, with macrophages, neutrophils and endothelial cells (EC) playing key roles. Extracellular vesicles have emerged as novel mediators of immune dysfunction across several immune pathologies. Microvesicles (MVs) are a class of extracellular vesicles that carry DAMPs, cytokines, and miRNAs, to regulate functions of recipient cells. We have found that MVs are a key reservoir for DAMPs, cytokines, and potent immune complexes after burn injury in humans and mice. Given our findings, and the key role of MVs in multiple immune conditions, we hypothesize that MVs drive the immune dysfunction associated with poor clinical outcomes in severe burn injury. These findings are highly synergistic with the Specific Aims of the parent grant. Using same patient and mouse tissue (utilizing our established pre-clinical model of burn and inhalation injury, and repository of human burn patient samples) derived during the parent grant’s experimental plan, we aim to further characterize the payload (Supplement Aim 1) and immune function (Supplement Aim 2) of MVs isolated from plasma after injury. This will allow us to incorporate MVs into the Immune Suppression Index (ISI) developed in the parent grant to identify burn patients at low and high risk for subsequent bacterial infection to improve prognostic value

抽象的 本多样性增刊中提出的研究和培训计划将建立在根据 博士前候选人 (Micah LaTrell Willis) 的家长申请。本研究计划及培训 提交的计划将为威利斯先生提供机会，不仅可以建立一个知识和技术工具箱， 推动他进入实习/发展的下一阶段，但为他提供职业发展 确保他实现短期和长期职业目标的机会。因此，从这个多样性的支持 补充品将使威利斯先生能够拥有并推动他的研究、培训和职业发展计划。 严重烧伤是最具破坏性的创伤形式之一，死亡率甚至高达 12% 在专门的烧伤中心。合并吸入性损伤进一步增加了死亡率。主要原因 死亡的主要原因是机会性感染，发生在受伤后数天至数周，通常导致致命 肺炎和/或菌血症引起的败血症。烧伤引起的免疫功能障碍是这种长期的基础 易受感染。众所周知，对细菌感染的反应是由 Toll 样诱导和调节的。 受体 (TLR) 和相关的 MyD88 信号传导，导致关键炎症细胞因子的释放。和我们的父母 NIGMS 授予“TLR/mTOR/PPARg 轴损伤诱导激活调节免疫反应” 烧伤和吸入性损伤后”（R01GM131124），我们目前正在人体和临床前研究 研究表明烧伤和吸入性损伤后的免疫功能障碍涉及 MyD88 介导的 TLR 异常 损伤后释放的损伤相关分子模式分子 (DAMP) 发出信号。这导致 细胞因子信号传导异常，其中巨噬细胞、中性粒细胞和内皮细胞 (EC) 发挥着关键作用。 细胞外囊泡已成为多种免疫系统中免疫功能障碍的新型介质 病理学。微泡 (MV) 是一类携带 DAMP、细胞因子和 miRNA 的细胞外囊泡， 调节受体细胞的功能。我们发现 MV 是 DAMP、细胞因子和 人类和小鼠烧伤后有效的免疫复合物。鉴于我们的发现以及 MV 在 多种免疫条件下，我们假设 MV 会导致与临床不良相关的免疫功能障碍 严重烧伤的结果。这些发现与家长的具体目标高度协同 授予。使用相同的患者和小鼠组织（利用我们建立的烧伤和吸入的临床前模型 伤害，以及人类烧伤患者样本的存储库）是在家长资助的实验计划中得出的，我们 旨在进一步表征MV的有效负载（补充目标1）和免疫功能（补充目标2） 受伤后从血浆中分离。这将使我们能够将 MV 纳入免疫抑制指数 (ISI) 在家长赠款中开发的目的是识别烧伤患者随后细菌感染的低风险和高风险 提高预后价值