Role of extraceullar vesicles in directing immunometabolic homeostasis after burn injury

摘要 本多样性补充文件中提出的研究和培训计划将建立在 博士预科生（Micah LaTrell Willis）的家长申请。本研究计划和培训 提交的计划将为Willis先生提供机会，不仅可以建立一个知识和技术工具箱， 推动他进入下一阶段的培训生/发展，但为他提供职业发展 这将有助于他实现短期和长期的职业目标。因此，这种多样性的支持 补充将授权威利斯先生拥有和推动他的研究，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%， 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 的死亡率是机会性感染，这些感染发生在受伤后几天到几周，通常导致致命的 肺炎和/或菌血症引起的败血症。烧伤诱导的免疫功能障碍是这种长期的 对感染的易感性已知对细菌感染的应答是由Toll样蛋白诱导和调节的。 受体（TLR）和相关的MyD 88信号传导，导致关键炎性细胞因子的释放。与我们的母 NIGMS授予“损伤诱导的TLR/mTOR/PPARg轴激活调节免疫反应 烧伤和吸入性损伤后”（R 01 GM 131124），我们目前正在人体和临床前研究 烧伤和吸入性损伤后的免疫功能障碍涉及异常MyD 88介导的TLR， 损伤后释放的损伤相关分子模式分子（DAMP）信号传导。这导致 异常的细胞因子信号传导，其中巨噬细胞、中性粒细胞和内皮细胞（EC）起关键作用。 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 病理学微囊泡（MV）是一类携带DAMP、细胞因子和miRNA的细胞外囊泡， 来调节受体细胞的功能。我们已经发现，MV是DAMP、细胞因子和 在人类和小鼠烧伤后的有效免疫复合物。鉴于我们的发现，以及MV在 多种免疫状况，我们假设MVs驱动与临床表现不佳相关的免疫功能障碍。 严重烧伤的后果。这些发现与母体的特定目标高度协同 格兰特.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 损伤，和人类烧伤患者样本库）在父母格兰特的实验计划中，我们 旨在进一步表征MV的有效载荷（补充目标1）和免疫功能（补充目标2） 从受伤后的血浆中分离。这将使我们能够将MV纳入免疫抑制指数（ISI） 在父母补助金中开发，以确定烧伤患者后续细菌感染的低风险和高风险， 改善预后价值

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