Role of extraceullar vesicles in directing immunometabolic homeostasis after burn injury

摘要 本多样性补编中提出的研究和培训计划将以下列项下产生的主要结论为基础 博士前候选人(Micah Latrell Willis)的家长申请。这项研究计划和培训 提交的计划将为威利斯先生提供机会，不仅可以建立一个智力和技术工具箱来 推动他进入实习生/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，来自这种多样性的支持 补充条款将使威利斯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。联合吸入性损伤进一步增加了这种死亡率。主要原因是 的死亡是机会性感染，发生在受伤后几天到几周，通常会导致致命 菌血症引起的肺炎和/或败血症。烧伤导致的免疫功能障碍是这种长期存在的基础 易受感染。已知对细菌感染的反应是由Toll样蛋白诱导和调节的 受体(TLR)和相关的MyD88信号，导致关键的炎性细胞因子的释放。和我们的父母 损伤诱导的TLR/mTOR/PPARg轴激活调节免疫应答 烧伤和吸入性损伤后“(R01GM131124)，我们目前正在对人体和临床前进行研究 烧伤和吸入性损伤后免疫功能障碍与MyD88介导的TLR异常有关的研究 损伤后释放的损伤相关分子模式分子(DAMP)发出的信号。这将导致 异常的细胞因子信号，巨噬细胞、中性粒细胞和内皮细胞(EC)起关键作用。 细胞外小泡已成为多种免疫功能障碍的新介质 病理学。微囊泡(MVS)是一类携带湿气、细胞因子和miRNAs的细胞外小泡， 调节受体细胞的功能。我们已经发现，MVS是阻滞剂、细胞因子和 人和小鼠烧伤后的有效免疫复合体。鉴于我们的发现，以及MVS在 多种免疫状况，我们假设MVS导致免疫功能障碍与临床不良相关 严重烧伤的后果。这些发现与父母的具体目标高度协同 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 伤害和人类烧伤患者样本库)是在父母赠款的实验计划期间得出的，我们 目的进一步描述MVS的有效载荷(补充目标1)和免疫功能(补充目标2) 从损伤后的血浆中分离。这将使我们能够将MVS纳入免疫抑制指数(ISI) 在家长赠款中开发，以确定烧伤患者后续细菌感染的低风险和高风险 提高预后价值

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