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 在这个NRSA个人博士前奖学金，以促进多样性提出的研究和培训计划， 健康相关的研究（F31）奖将支持我们的博士前候选人Micah LaTrell Willis，目前的第三位 我是查佩尔山的北卡罗来纳州大学的一年研究生。我们收到了多样性补充， NIGMS R 01奖（R 01 GM 131124），使Willis先生能够获得持续的支持， 表现得非常出色。本研究计划和提交的培训计划将为Willis先生提供 机会，不仅建立一个知识和技术工具箱，以推动他对他的下一阶段， 培训生/发展，但提供他的职业发展机会，以确保他获得他的短期和 长期职业目标。因此，F31的支持将使威利斯先生能够拥有和推动他的研究， 培训和职业发展计划。 烧伤是最具破坏性的创伤形式之一，死亡率高达12%， 并发症，如器官衰竭、肺炎和其他器官感染。烧伤导致双相性 系统性免疫功能障碍首先，早期（0-72小时）的高度炎症状态，伴随着增加的 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。之后是免疫抑制期（周/周）。 损伤后数月）与广泛增加的感染易感性相关。这种免疫抑制 阶段与抗炎细胞因子和外周髓源性 来自骨髓的抑制性细胞（MDSC），已被证明发挥关键的免疫调节作用 通过抑制T细胞反应和调节细胞因子的产生来治疗创伤性损伤。迫切需要 进一步表征烧伤中的这种细胞类型，并确定烧伤后它们产生的机制。 细胞外囊泡已经成为几种免疫系统中免疫功能障碍的新型介质 病理学细胞外囊泡（EV）携带DAMPs、细胞因子和miRNAs，以调节受体的功能， 细胞我们已经发现，EV是DAMP、细胞因子和有效免疫复合物的关键储存库， 人和小鼠的烧伤。鉴于我们的发现，以及EV在多种免疫状况中的关键作用，我们 假设EV驱动与严重烧伤不良临床结局相关免疫功能障碍。 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储存库）， 收集的人类烧伤患者样本），我们旨在进一步表征有效载荷， 确定它们作为免疫功能障碍的生物标志物的用途，以及免疫功能（目的1）和细胞免疫的影响。 损伤后从血浆中分离的EV的稳态（目的2）。