Neutrophils and polytrauma - from recruitment to phenotypic and functional reprogramming

摘要 斑马鱼动物模型提供了一个独特的机会，可视化，跟踪和反卷积的分子 在整个动物背景下，多发性创伤中中性粒细胞反应的机制。光学 这种小型脊椎动物系统的遗传和药理学操作的透明度和容易性已经成为 它是研究中性粒细胞和损伤的有力工具，在过去十年中有无数关键发现。在此我们 建议评估1）协调中性粒细胞募集的调节机制，以并发创伤 2）中性粒细胞如何在创伤性损伤部位重编程以产生特定的中性粒细胞亚群 在创伤中逆转迁移和传播炎症，以及3）慢性炎症如何影响这种 流程.我们将联合收割机整体动物非侵入性活体成像方法与基因操作相结合， 中性粒细胞的蛋白质、脂质、转录物和表观遗传学分析。我们的研究将使我们能够更深入地了解 了解中性粒细胞参与多发性创伤炎症反应的机制， 后炎症设置。我们的实验室有超过120条斑马鱼转基因和突变品系，使我们能够 可视化和基因操作中性粒细胞。最近发现的果蝇感染正在造成不适当的 这些条件对我们的工作特别重要，危及我们的研究计划， 家长补助金此外，我们还遇到了其他空间问题，这些问题将限制我们的研究 一旦我们扩大我们的计划（目前在95%的能力）。我们的研究项目有一个独特的工作领域 与我们的模型，工具和技能相一致的，将为多发性创伤领域的重要知识做出贡献。 损伤这些知识将使我们能够操纵中性粒细胞反应，作为改善患者 创伤后的结果，特别是在高危人群中。

Abstract The zebrafish animal model provides a unique opportunity to visualize, track and deconvolute the molecular mechanism involved in the neutrophil response in polytrauma at a whole-animal context. The optical transparency and ease of genetic and pharmacological manipulation of this small vertebrate system has become a powerful tool to study neutrophils and injury, with innumerous key findings in the last decade. Herein we propose to evaluate 1) the regulatory mechanisms that coordinate neutrophil recruitment to concurrent traumatic injuries, 2) how neutrophils are reprogrammed at sites of traumatic injury to generate specific neutrophil subsets that reverse migrate and disseminate inflammation in trauma, and 3) how chronic inflammation impacts such processes. We will combine whole-animal non-invasive live imaging approach with genetic manipulation and protein, lipid, transcript, and epigenetic profiling of neutrophils. Our research will allow us to gain a deeper understanding of the neutrophil mechanisms involved in polytrauma inflammatory response in healthy and metainflammation settings. Our lab has over 120 lines of zebrafish transgenic and mutant lines that allow us to visualize and genetically manipulate neutrophils. A recent detected fruit fly infestation is creating improper conditions that are particularly concerning for our line of work, jeopardizing our research program supported by the parent grant. Moreover, we are also encountering additional space issues that will be limiting our research soon as we expand our program (currently at 95% capacity). Our research program has a unique line of work that aligned with our models, tools and skills will contribute with significant knowledge to the field of polytraumatic injury. This knowledge will enable us to manipulate neutrophil response as a means by which to improve patient outcomes following trauma, particularly in high-risk groups.