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.

项目总结/摘要 烧伤仍然是美国意外死亡和受伤的主要原因之一。 非致命性烧伤是发病的主要原因，最常见的并发症是感染 相关.热损伤导致炎症和免疫反应的巨大波动（例如，血浆 细胞因子、细胞表型、免疫功能和可溶性蛋白），这些变化与 死亡率和感染并发症。然而，驱动这些功能失调的潜在机制 在系统和地方两方面，反应在很大程度上仍然未知。我们的主要目标是调查 和小儿热损伤后免疫功能障碍的局部机制，以提供有用的生物标志物 确定那些最有可能发生后续感染的人，目标是开发治疗方法， 患者结局。在接下来的五年里，我们将实施三项综合研究计划， 血液和组织样品以及建立的烧伤和感染的幼年鼠模型， 探讨烧伤后免疫功能紊乱的机制。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 淋巴细胞共抑制分子的表面表达，检测分离的淋巴细胞上的凋亡标记物， 并进行功能测定。这项工作将提供深入了解周围淋巴细胞的机制， 并指导未来的免疫调节疗法，可以针对这些特定的机制。研究 计划2将评估严重烧伤后全身单核细胞向组织巨噬细胞的分化， 烧伤后并发症在这项工作中，我们将进行功能测定分离的系统单核细胞 群体和分离的组织巨噬细胞。这项工作将使我们得到一个更完整的机械 了解全身单核细胞群分化为伤口中的局部巨噬细胞 睡觉了该信息将告知施用免疫调节剂的最佳施用途径（全身或局部）。 治疗以增加这些巨噬细胞并改善组织水平结果。研究计划3将阐明 FDA批准的免疫调节剂治疗在严重烧伤后预防烧伤后的潜在益处 并发症这项工作将使用联合疗法，在儿科样品中离体和在我们的小鼠中体内 烧伤模型，以评估免疫功能的变化。这项研究的发现对于推动 在该人群中设计未来的免疫刺激临床试验以及其他形式的外科手术 易患败血症，如创伤和大手术。此外，这也可以作为其他年龄段的榜样。 烧伤组。这些项目将共同为发展中国家提供一个重要的组成部分， 在治疗烧伤伤口中的合适的治疗剂，其可以同时帮助控制炎症、预防 感染，并帮助伤口愈合，这是烧伤护理研究的绝对必要条件。