Pathologic Myeloid Activation in Pediatric Burn Injury

小儿烧伤中的病理性骨髓激活

• 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
• 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

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.”

摘要