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Systemic and Local Immune Function after Pediatric Thermal Injury

小儿热损伤后的全身和局部免疫功能

基本信息

批准号：
9768513
负责人：
Rajan Thakkar
金额：
$ 18.85万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9768513
关键词：
Adult Advisory Committees American Anti-inflammatory Antibodies Antigen-Presenting Cells Area Beds Biological Assay Blood specimen Burn Centers Burn injury Cancer Patient Caring Cells Cessation of life Child Childhood Clinical Clinical Trials Critical Illness Data Debridement Development Disease Down-Regulation FDA approved Flow Cytometry Funding Future Goals Granulocyte-Macrophage Colony-Stimulating Factor Immune Immune checkpoint inhibitor Immunobiology Immunohistochemistry Immunologic Adjuvants Immunologic Surveillance Immunosuppression Immunotherapy Incubated Infection Inflammatory Inflammatory Response Injury Interleukin-7 K-Series Research Career Programs Knowledge Laboratories Leukocytes Ligands Link Lymphocyte Malignant Neoplasms Measures Mentors Mentorship Messenger RNA Methods Morbidity - disease rate Nosocomial Infections Ohio Organ Transplantation Outcome Pathway interactions Pediatric Hospitals Phenotype Population Prevalence Recombinants Recording of previous events Reporting Research Research Institute Research Personnel Research Training Risk Role SLEB2 gene Sampling Scientist Sepsis Skin graft Surgeon Testing Therapeutic Time Tissues Training Trauma United States Universities Up-Regulation Work Wound Healing Wound Infection adverse outcome career clinical development design experimental study graft failure heat injury immune checkpoint immune function immunoregulation improved outcome infection risk inhibitor/antagonist injured injured children laser capture microdissection macrophage mortality mortality risk new therapeutic target outcome prediction patient population pediatric burn injury pediatric patients peripheral blood phenotypic biomarker programs receptor expression restoration septic tool wound

项目摘要

PROJECT SUMMARY/ABSTRACT Given the prevalence and morbidity of pediatric thermal injury it is imperative that we completely understand and define all knowledge gaps related to this disease. The immunobiology of pediatric burn injury is not well defined and if understood can unlock the doors to novel therapeutic targets. My prior research training, current research advisory committee, strong mentorship and practice as a pediatric burn surgeon will allow me to obtain data and help close this knowledge gap. The overall objective of this proposal is to further develop my career into a surgeon-scientist whose focus is on the immunobiology of pediatric thermal injury with goals of using immunomodulation therapy to decrease adverse outcomes. Using methods validated in other forms of pediatric critical illness we will test our central hypothesis that upregulation of the PD-1 pathway is associated with immune suppression and adverse outcomes following pediatric burn injury; and that this immune suppression is reversible ex vivo through the use of PD-1 pathway inhibitors. Thermally injured children will undergo longitudinal blood sampling as well as tissue bed sampling at the time of debridement and grafting procedures. Leukocyte expression of PD-1/PD-L1/L2 will be quantified by flow cytometry. Innate and adaptive immune function will be measured by ex vivo stimulation assays and flow cytometry. Wound bed macrophage expression of PD-1/PD-L1/L2 will be measured along with pro- inflammatory and anti-inflammatory phenotypic markers using immunohistochemistry and laser capture microdissection with mRNA profiling. Furthermore, we will determine if the immune suppressive effects of thermal injury are reversible using ex vivo methods. We will co-incubate peripheral blood leukocytes from thermally injured children with inhibitors of the PD-1 pathway, GM-CSF or recombinant IL-7. Cells will then be evaluated for restoration of immune function via ex vivo stimulation assays and flow cytometry. This study will be the first to evaluate the role of the PD-1 pathway with respect to pediatric thermal injury. This is of particular importance given the clinical implications of immune checkpoint inhibitors in other forms of disease such as cancer and sepsis. This career development award will generate further preliminary data and also provide me with the tools necessary to successfully compete for future independent funding in areas of pediatric thermal injury.

项目总结/文摘