Neutrophils and polytrauma - from recruitment to phenotypic and functional reprogramming

中性粒细胞和多发伤 - 从招募到表型和功能重编程

• 批准号: 10797986
• 负责人: SOFIA DE OLIVEIRA
• 金额: $ 24.99万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10797986
• 关键词: Animal Model; Animals; Behavior; Chronic; Diet; Drosophila genus; Genetic; Inflammation; Inflammatory Response; Injury; Knowledge; Lipids; Metabolic syndrome; Modeling; Molecular; Multiple Trauma; Neutrophil Infiltration; Optics; Organ; Pathologic; Patient-Focused Outcomes; Pattern; Phenotype; Play; Predisposition; Process; Proteins; Research; Role; Site; System; Tissues; Transcript; Transgenic Organisms; Trauma; Traumatic injury; Visualization; Work; Zebrafish; epigenetic profiling; genetic manipulation; high risk population; imaging approach; improved; migration; mutant; neutrophil; parent grant; pharmacologic; programs; recruit; response; skills; targeted treatment; tool

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.

抽象的 斑马鱼动物模型提供了一个独特的机会，可以可视化，跟踪和反应分子 在整个动物环境中，多发性疾病中嗜中性粒细胞反应涉及的机制。光学 该小脊椎动物系统的透明度和遗传和药理学操纵的便利性已成为 在过去的十年中，研究中性粒细胞和伤害的有力工具，具有无数的关键发现。在这里我们 提议评估1）协调中性粒细胞募集到并发创伤的调节机制 受伤，2）如何在创伤性损伤部位重编程中性粒细胞以产生特定的中性粒细胞亚群 这种反向迁移并传播创伤中的炎症，3）慢性炎症如何影响这种 过程。我们将结合全动物非侵入性实时成像方法与遗传操作和 中性粒细胞的蛋白质，脂质，转录和表观遗传分析。我们的研究将使我们更加深入 了解健康和 元炎症设置。我们的实验室有超过120行的斑马鱼转基因和突变线，使我们能够 可视化和遗传操纵中性粒细胞。最近发现的果蝇侵扰正在造成不当 对于我们的工作范围特别关注的条件，危害我们的研究计划的支持 父母赠款。此外，我们还遇到其他空间问题，这些问题将限制我们的研究 一旦我们扩大计划（目前为95％的容量）。我们的研究计划有独特的工作 这与我们的模型，工具和技能一致，这将为多发性领域带来重要的知识 受伤。这些知识将使我们能够操纵中性粒细胞反应，以此来改善患者 创伤后的结果，特别是在高风险群体中。