Pathologic Myeloid Activation in Pediatric Burn Injury

小儿烧伤中的病理性骨髓激活

基本信息

批准号：
10673601
负责人：
Shawn David Larson
金额：
$ 19.06万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10673601
关键词：
15 year old 5 year old Acute Address Adolescent Adult Age Appearance Attention Blood Blood specimen Body Surface Area Burn injury Cell Count Cell physiology Cellular Indexing of Transcriptomes and Epitopes by Sequencing Child Childhood Chronic Clinical Development Enrollment Ensure Evolution Flow Cytometry Foundations Functional disorder Genetic Goals HLA-DR Antigens Hematopoiesis Homeostasis Hospitalization ITGAM gene Immune System Diseases Immune response Immunity Immunosuppression Impairment Inflammation Inflammatory Response Injury Interferon Type II Kinetics Knowledge Leukocytes Lymphocyte Lymphocyte Count Lymphocyte Function Lymphoid Lymphoid Cell Lymphopenia Macrophage Malignant Neoplasms Measures Mononuclear Morbidity - disease rate Myelogenous Myeloid Cells Myeloid-derived suppressor cells Nosocomial Infections Outcome Pathologic Patients Phenotype Pilot Projects Population Populations at Risk Predisposition Preschool Child Production Productivity Propranolol Rheumatoid Arthritis Role Secondary to Sepsis System T-Cell Proliferation T-Lymphocyte TNF gene Testing Time Trauma patient Vulnerable Populations Width age group age related body system burn therapy cohort cost design heat injury high reward immune function lymphocyte proliferation monocyte mortality risk novel outcome prediction patient subsets pediatric burn injury pediatric patients pediatric trauma personalized approach personalized intervention personalized medicine psychologic response septic patients single-cell RNA sequencing transcriptome transcriptomics treatment strategy

项目摘要

ABSTRACT Burn injury is a leading cause of trauma in children, resulting in life-long physical and psychological morbidities. Young children, particularly those under 5-years of age, represent a highly vulnerable and at-risk population for an exaggerated systemic host response leading to multiple organ system dysfunction (MODS). Unfortunately, much of our current burn treatment strategies are extrapolated from adult studies or are broadly applied across the age spectrum. These approaches fail to consider the unique host immune responses of pediatric patients across the different age stages of childhood. Understanding age-specific immune dysfunction resulting from pediatric burn injury will address a key gap of knowledge necessary to develop novel personalized interventions for this highly vulnerable population. Our overarching hypothesis is that burn injury induces pathologic myeloid activation in the pediatric host, resulting in expansion of myeloid-derived suppressor cells (MDSCs), suboptimal monocyte function, lymphopenia and lymphocyte dysfunction. Additionally, we believe this effect is both age- and burn size-dependent, such that younger patients more commonly enter a state of pathologic myeloid activation with increased susceptibility to burn sepsis and immunosuppression. We have two specific aims: 1) to determine whether pediatric burn injury leads to pathologic myeloid activation, increasing circulating immunosuppressive MDSCs, engendering dysfunctional monocyte and decreasing lymphocyte numbers and function; and, 2) to examine whether pediatric burn injury induces a unique blood myeloid and lymphoid transcriptome in young and older pediatric patients with small and larger burns that can explain the functional and phenotypic changes. To achieve these goals, we intend to enroll two pediatric burn patient cohorts differing in their age and burn size. We intend to compare children 1–5 years old (n=30) with either small (<15% TBSA, n=15) or larger (15-30% TBSA, n=15) burns, with children 9-15 years old (n=30) with TBSA-matched burn sizes (n=15 each), and age-matched non-injured controls (n=30). Using flow cytometry, we will determine how MDSC numbers and phenotypes are influenced by pediatric age and burn size over time. Similarly, we will investigate MDSC numbers and function in relation to susceptibility to and loss of T-cell proliferation and IFNγ production (ELISpot). Additionally, we will determine changes in blood monocyte HLA-DR expression, monocyte distribution width (MDW) and quantify ex vivo stimulated mononuclear TNF-α production (ELISpot). In a subset of these patients, we will perform single cell RNA-seq/CITE-Seq (Cellular Indexing of Transcriptomes and Epitopes by Sequencing) of blood myeloid and lymphoid cells in the early (day 4) and later (day 30) periods after burn injury. Our ultimate goal is to develop novel treatment paradigms that treat children with a personalized approach ensuring that this vulnerable population “…achieve(s) their full potential for healthy productive lives.”

抽象的烧伤是儿童创伤的主要原因，会导致终生的身体和心理疾病。幼儿，特别是 5 岁以下的儿童，是高度脆弱和高危人群过度的全身宿主反应导致多器官系统功能障碍（MODS）。我们目前的许多烧伤治疗策略都是从成人研究中推断出来的，或者广泛应用于各个领域这些方法未能考虑儿科患者独特的宿主免疫反应。了解儿童不同年龄阶段造成的年龄特异性免疫功能障碍。儿科烧伤将解决开发新型个性化干预措施所需的关键知识空白对于这个高度脆弱的人群，我们的首要假设是烧伤会诱发病理性骨髓细胞。儿科宿主中的激活，导致骨髓源性抑制细胞 (MDSC) 扩张，未达最佳状态此外，我们认为这种影响与年龄有关。且烧伤面积依赖性，因此年轻患者更常进入病理性骨髓状态激活与烧伤败血症和免疫抑制的易感性增加我们有两个具体目标：1）确定小儿烧伤是否会导致病理性骨髓激活，增加循环免疫抑制 MDSC，导致单核细胞功能障碍并减少淋巴细胞数量功能；以及，2) 检查小儿烧伤是否会诱发独特的血液骨髓和淋巴年轻和老年小儿和大面积烧伤儿童患者的转录组可以解释功能性烧伤为了实现这些目标，我们打算招募两个不同的儿童烧伤患者队列。我们打算将 1-5 岁儿童 (n=30) 与较小的 (<15% TBSA、 n=15) 或更大 (15-30% TBSA，n=15) 烧伤，其中 9-15 岁儿童 (n=30) 具有与 TBSA 相匹配的烧伤面积（每人 n=15）和年龄匹配的未受伤对照（n=30），我们将使用流式细胞术确定 MDSC 的情况。随着时间的推移，数量和表型受到儿科年龄和烧伤面积的影响。我们将进行类似的调查 MDSC 数量和功能与 T 细胞增殖和 IFNγ 产生的易感性和丧失相关 (ELISpot) 此外，我们还将确定血液单核细胞 HLA-DR 表达、单核细胞分布的变化。宽度 (MDW) 并量化离体刺激的单核 TNF-α 产生 (ELISpot)。对于患者，我们将进行单细胞 RNA-seq/CITE-Seq（转录组和表位的细胞索引）烧伤后早期（第 4 天）和后期（第 30 天）的血液骨髓细胞和淋巴细胞测序。我们的最终目标是开发新颖的治疗范例，以个性化的方法治疗儿童确保这一弱势群体“……充分发挥潜力，过上健康、富有成效的生活。”