Role of extracellular vesicles in assaying and regulating immune dysfunction after burn injury

细胞外囊泡在测定和调节烧伤后免疫功能障碍中的作用

• 批准号: 10607063
• 负责人: Micah LaTrell Willis
• 金额: $ 1.55万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10607063
• 关键词: 3-Dimensional; Acute; Acute-Phase Reaction; Address; Adoptive Transfer; Affect; Anti-Inflammatory Agents; Antigen-Antibody Complex; Award; Bacterial Infections; Biological Assay; Biological Markers; Biological Response Modifiers; Body Surface Area; Bone Marrow; Burn injury; CCL2 gene; Cell Differentiation process; Cell physiology; Cells; Clinical; Coculture Techniques; Compensation; Data; Development; Development Plans; Disease; Ensure; Fellowship; Frequencies; Functional disorder; Generations; Goals; HMGB1 gene; Harvest; Health; Hematopoietic stem cells; Homeostasis; Hour; Human; IL8 gene; Immune; Immune System Diseases; Immune response; Immunologic Markers; In Vitro; Individual; Infection; Inflammatory; Injections; Injury; Interleukin-1 beta; Interleukin-10; Interleukin-6; Laboratories; Length of Stay; Lipids; Macrophage; Membrane; MicroRNAs; Molecular; Multiple Organ Failure; Mus; Myeloid Cells; Myeloid-derived suppressor cells; National Institute of General Medical Sciences; National Research Service Awards; Nature; North Carolina; Nucleic Acids; Organ; Organ failure; Outcome; Pathology; Patient-Focused Outcomes; Patients; Pattern; Peripheral; Phagocytosis; Phase; Phenotype; Plasma; Play; Pneumonia; Pre-Clinical Model; Predisposition; Production; Proteins; Proteomics; Publishing; Reporting; Research; Role; Sampling; Sepsis; Severities; Source; Structure; T cell response; T-Lymphocyte; Tail; Testing; Time; Tissues; Training; Trauma; Traumatic injury; Universities; Veins; career; career development; cell type; cytokine; empowerment; exposed human population; extracellular vesicles; functional outcomes; graduate student; hematopoietic stem cell differentiation; immune function; immunoregulation; immunosuppressed; mortality; nanoparticle; neutrophil; novel; pre-doctoral; repository; response; severe burns; stem cells; third degree burn; vesicular release

ABSTRACT The research and training plan put forth in this NRSA Individual Predoctoral Fellowships to Promote Diversity in Health-Related Research (F31) Award will support our pre-doctoral candidate Micah LaTrell Willis, a current third year graduate student at the University of North Carolina at Chapel Hill. We received a Diversity Supplement for a NIGMS R01 Award (R01GM131124) which enabled Mr Willis to receive continued support, and he has performed excellently. 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 F31 will empower Mr. Willis to own and drive his research, training, and career development plans. Burn injury is one of the most devastating forms of trauma, with high mortality rates up to 12% due to complications such as organ failure, pneumonia, and infections of other organs. Burn injury results in biphasic systemic immune dysfunction. First, an early (0-72 hours) hyper-inflammatory state, with increased release of immunostimulatory Damage Associated Molecular Patterns (DAMPs) and pro-inflammatory cytokines which can lead to barrier dysfunction and multiple organ failure. Following this is an immunosuppressive phase (weeks / months after injury) associated with widespread increased susceptibility to infection. This immunosuppressed phase is associated with anti-inflammatory cytokines and increased frequency of peripheral myeloid-derived suppressive cells (MDSC) from the bone marrow, which have been shown to play key immunoregulatory roles after traumatic injury by suppressing T cell responses and regulating cytokine production. There is a critical need to characterize this cell type further in burn injury and define the mechanism of their generation after burn injury. Extracellular vesicles have emerged as novel mediators of immune dysfunction across several immune pathologies. Extracellular vesicles (EV) carry DAMPs, cytokines, and miRNAs, to regulate functions of recipient cells. We have found that EVs 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 EVs in multiple immune conditions, we hypothesize that EVs drive the immune dysfunction associated with poor clinical outcomes in severe burn injury. Using same patient and mouse tissue (utilizing our established pre-clinical model of burn injury, and repository of collected human burn patient samples) that we have collected we aim to further characterize the payload, to determine their use as biomarkers of immune dysfunction, and immune function (Aim 1) and effect of cellular homeostasis (Aim 2) of EVs isolated from plasma after injury.

摘要 NRSA个人博士前奖学金中提出的研究和培训计划，以促进 健康相关研究(F31)奖将支持我们的博士前候选人Micah Latrell Willis，目前排名第三 北卡罗来纳大学教堂山分校一年级研究生。我们收到了一份多样性补充资料， NIGMS R01奖(R01GM131124)，使Willis先生获得持续支持，他已经 表现出色。本研究计划和提交的培训计划将为Willis先生提供 机会不仅是建立一个智力和技术工具箱，推动他迈向下一阶段的 实习生/发展，但为他提供职业发展机会，以确保他获得短期和 长期的职业目标。因此，这款F31的支持将赋予威利斯先生拥有和推动他的研究的权力， 培训和职业发展计划。 烧伤是最具破坏性的创伤形式之一，高死亡率高达12%，原因是 并发症，如器官衰竭、肺炎和其他器官感染。烧伤导致双相 全身性免疫功能障碍。首先，早期(0-72小时)高炎症状态，释放更多的 免疫刺激损伤相关分子模式(DAMP)和促炎细胞因子 导致屏障功能障碍和多器官衰竭。接下来是免疫抑制阶段(周/ 受伤后几个月)与普遍增加的感染易感性有关。这种免疫抑制 时相与抗炎细胞因子和外周髓系来源的频率增加相关 来自骨髓的抑制细胞(MDSC)，已被证明发挥关键的免疫调节作用 在创伤后，通过抑制T细胞反应和调节细胞因子的产生。有一种迫切的需要 目的：进一步明确烧伤后这种细胞类型的特征，并明确其发生机制。 细胞外小泡已成为多种免疫功能障碍的新介质 病理学。细胞外小泡(EV)携带阻滞剂、细胞因子和miRNAs，以调节受体的功能 细胞。我们已经发现，EV是湿气、细胞因子和强大的免疫复合体的关键储存库，在 烧伤对人和小鼠的伤害。鉴于我们的发现，以及EVS在多种免疫条件下的关键作用，我们 假设EVS导致严重烧伤患者的免疫功能障碍与不良的临床结局相关。 使用相同的患者和小鼠组织(利用我们建立的烧伤临床前模型和存储库 我们收集的人类烧伤患者样本)，我们的目标是进一步表征有效载荷，以 确定它们作为免疫功能障碍和免疫功能的生物标志物的用途(目标1)和细胞的影响 损伤后血浆分离EVS的动态平衡(目标2)。