Elucidating the Mechanisms of Immune Dysfunction After Severe Burn Injury

阐明严重烧伤后免疫功能障碍的机制

• 批准号: 10711888
• 负责人: Rajan Thakkar
• 金额: $ 39万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10711888
• 关键词: Acute; Adolescent; Affect; Apoptotic; Automobile Driving; Biological Assay; Biological Markers; Blood specimen; Burn injury; Caring; Cell surface; Cessation of life; Childhood; Clinical Trials; Combined Modality Therapy; FDA approved; Functional disorder; Future; Goals; Immune System Diseases; Immune response; Infection; Infection prevention; Inflammation; Inflammatory Response; Injury; Lymphocyte; Macrophage; Modeling; Morbidity - disease rate; Mus; Operative Surgical Procedures; Outcome; Patient-Focused Outcomes; Persons; Phenotype; Plasma; Population; Predisposition; Proteins; Public Health; Research; Route; Sampling; Sepsis; Therapeutic; Tissue Sample; Tissues; Trauma; United States; Work; age group; burn model; burn wound; cytokine; design; heat injury; high risk; immune function; immunomodulatory therapies; improved; improved outcome; in vivo; insight; monocyte; mortality; mouse model; prevent; response; severe burns; severe injury; therapy development; wound bed; wound healing

Project Summary/Abstract Burn injuries continue to be one of the leading causes of unintentional death and injury in the United States. Non-fatal burn injuries are a leading cause of morbidity with the most common complications being infectious related. Thermal injures result in massive fluctuations in the inflammatory and immune responses (e.g., plasma cytokines, cellular phenotypes, immune function, and soluble proteins) and these changes have been associated with mortality and infectious complications. However, the underlying mechanisms driving these dysfunctional responses is still largely unknown both systemically and locally. Our primary goal is to investigate the systemic and localized mechanisms of immune dysfunction following pediatric thermal injury to provide useful biomarkers to identify those at highest risk to develop subsequent infection with a goal to develop therapies to improve patient outcomes. Over the next five years we will pursue three integrated research plans that use both pediatric blood and tissue samples as well as an established juvenile murine model of burn injury and infection, to investigate the mechanisms of immune dysfunction after burn injury. Research Plan 1 will investigate the mechanisms underlying lymphocyte dysfunction after severe burn injury. In this work we will assess the cell surface expression of lymphocyte co-inhibitory molecules, examine apoptotic markers on isolated lymphocytes, and perform functional assays. This work will provide insight into the mechanisms surrounding lymphocyte dysfunction and guide future immunomodulatory therapies that can target these specific mechanisms. Research Plan 2 will evaluate the differentiation of systemic monocytes to tissue macrophages after severe burn injury and post-burn complications. In this work we will perform functional assays on isolated systemic monocyte populations and isolated tissue macrophages. This work will lead us to a more complete mechanistic understanding of the differentiation of systemic monocyte populations to the localized macrophages in the wound bed. This information will inform the best route of administration (systemic or topical) to apply immunomodulatory therapy to augment these macrophages and improve tissue level outcomes. Research Plan 3 will elucidate the potential benefits of FDA-approved immunomodulator therapies after severe burn injury to prevent post-burn complications. This work will use combination therapies, ex vivo in pediatric samples and in vivo in our murine burn model, to assess changes in immune function. The findings from this study will be important to advance the design of future immunostimulatory clinical trials in this population as well as other forms of surgical predisposition to sepsis such as trauma and major surgery. Moreover, this could serve as a model for other age groups of burn injuries. Together, these projects will provide an important building block for developing appropriate therapeutics in treating burn wounds that can simultaneously help control inflammation, prevent infection, and assist in wound healing, which is an absolute necessity for burn care research.

项目摘要/摘要 烧伤仍然是美国无意死亡和伤害的主要原因之一。 非致命烧伤受伤是发病率的主要原因，最常见的并发症是感染力 有关的。热损伤导致炎症和免疫反应的大规模波动（例如等离子体 细胞因子，细胞表型，免疫功能和可溶性蛋白），这些变化已与 死亡率和感染性并发症。但是，驱动这些功能失调的基本机制 在系统和本地，响应在很大程度上都是未知的。我们的主要目标是调查系统 小儿热损伤后免疫功能障碍的局部机制可提供有用的生物标志物 确定那些有最高风险的人，以发展后续感染，以开发疗法以改善 患者的结果。在接下来的五年中，我们将遵循三个使用两种儿科的综合研究计划 血液和组织样本以及已建立的烧伤和感染的少年鼠模型 研究烧伤后免疫功能障碍的机制。研究计划1将调查 严重烧伤后淋巴细胞功能障碍的机制。在这项工作中，我们将评估细胞 淋巴细胞共抑制性分子的表面表达，检查分离的淋巴细胞上的凋亡标志物， 并执行功能测定。这项工作将洞悉淋巴细胞周围的机制 功能障碍并指导可以针对这些特定机制的未来免疫调节疗法。研究 计划2将评估严重烧伤损伤和 燃烧后并发症。在这项工作中，我们将对孤立的全身单核细胞进行功能测定 种群和孤立的组织巨噬细胞。这项工作将使我们达到更完整的机械 了解全身单核细胞种群与伤口局部巨噬细胞的分化 床。此信息将告知最佳管理途径（系统或局部）以应用免疫调节 治疗以增加这些巨噬细胞并改善组织水平的结果。研究计划3将阐明 严重烧伤损伤后，由FDA批准的免疫调节剂疗法的潜在益处以防止燃烧后 并发症。这项工作将使用组合疗法，小儿样品中的体内和在我们的鼠中的体内 燃烧模型，以评估免疫功能的变化。这项研究的发现对于推进 该人群以及其他形式的手术的未来免疫刺激临床试验的设计 败血症（例如创伤和大型手术）的易感性。而且，这可以作为其他年龄的模型 一组烧伤。这些项目将共同为开发提供一个重要的基础 适当治疗可以同时帮助控制炎症的烧伤伤口的适当治疗剂 感染并有助于伤口愈合，这绝对是烧伤护理研究的必要性。