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Principal Investigator: Eric Anthony Sribnick
Organization: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
Fiscal Year: 2024
Award: $187,635
Funding agency: National Institute of Neurological Disorders and Stroke
PROJECT SUMMARY/ABSTRACT
Critical injury, including traumatic brain injury (TBI), remains one of the most common causes of morbidity and
mortality in children. Despite efforts to develop pharmacotherapy for TBI, clinical trials have proven ineffective.
Improvements in outcome have largely been due to improvements in medical care. One known complication of
severe TBI is nosocomial infection; the incidence may be as high as 50% with mortality as high as 37%. Even in
the absence of mortality, infection can lead to secondary brain injury and poor outcomes. One cause for post-
injury nosocomial infections is a profound anti-inflammatory response known as immunoparalysis. TBI is strongly
associated with immunoparalysis, and more recent data suggest that patients with TBI plus systemic injury
(polytrauma) are even more prone to nosocomial infection than patients with either injury alone. One pathway
by which this may occur is through a neurally-mediated mechanism known as the cholinergic anti-inflammatory
pathway (CAIP), which involves signaling from the brain to splenic leukocytes via the splenic nerve. Attenuation
of the CAIP is a potential method for reversing immunoparalysis, but other therapeutic targets include
mechanism-independent immunomodulation. Unfortunately, there is little preclinical data examining the timeline
for immune suppression following injury or how reversing post-injury immune suppression may affect the injured,
recovering brain. The overall goal of this proposal is to develop immunomodulatory approaches to improve
outcomes through safe restoration of immune function following critical injury in children. Our central
hypothesis is that post-injury immune suppression is an important acute and chronic sequela of critical
injury that can be attenuated without negatively impacting neurological outcomes. Experiments will
involve using a clinically relevant combined injury model in juvenile rats: an experimentally induced TBI
(controlled cortical impact) followed by hemorrhage induced by aspiration of blood from the femoral artery. To
perform mechanism-specific attenuation of post-traumatic immunosuppression, we propose using splenic
denervation to inhibit the CAIP. As splenic denervation is clinically not practical, we will also use
pharmacotherapeutic agents to target the CAIP, including treatment with an α7 nicotinic receptor antagonist
(memantine) or a beta-adrenergic antagonist (propranolol). We will also examine mechanism-independent
pharmacotherapy of post-traumatic immune suppression using several immunostimulants (GM-CSF, rIL-7, INF
ɣ, and anti-PD-1). Finally, as the long-term immunologic effects of severe traumatic injury are poorly understood,
we will quantify the persistence of immunosuppressive effects of severe trauma in both our TBI/H model and in
critically injured children. This career development award will generate further preliminary data and provide me
with the necessary tools to obtain research independence and further funding in the area of pediatric
neurotrauma.
Terms: <0-11 years old><Acquired brain injury><Acute><Adolescent><Adolescent Youth><Adrenergic beta-Antagonists><Adrenergic beta-Blockers><Affect><Animal Model><Animal Models and Related Studies><Animals><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Area><Attenuated><Bleeding><Blood><Blood Reticuloendothelial System><Blood leukocyte><Brain><Brain Injuries><Brain Nervous System><Brain Trauma><CNS Injury><CNS Nervous System><Career Development Awards><Career Development Awards and Programs><Career Development Programs K-Series><Caring><Cause of Death><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cellular Immune Function><Central Nervous System><Cephalic><Child><Child Youth><Childhood><Childhood Injury><Children (0-21)><Chronic><Clinical><Clinical Trials><Cognition><Cognitive><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Common Rat Strains><Complication><Cranial><Critical Illness><Critically Ill><Data><Denervation><Development><Disturbance in cognition><Drug Therapy><Drugs><Elements><Encephalon><Enrollment><Foundations><Funding><GM-CSF><Goals><Granulocyte-Macrophage Colony-Stimulating Factor><Hemorrhage><Histamine-Producing Cell-Stimulating Factor><Hospital Infections><Hospital acquired infection><Human><Hypovolemia><Hypovolemics><IFN-Gamma><IFN-g><IFN-γ><IFNG><IFNγ><IL-7><IL-7 Gene><IL7><IL7 Protein><IL7 gene><Immune><Immune Interferon><Immune Targeting><Immunes><Immunoactivators><Immunoadjuvants><Immunochemical Immunologic><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Immunologic><Immunologic Adjuvants><Immunologic Subtyping><Immunological><Immunologically><Immunologics><Immunology><Immunomodulation><Immunophenotyping><Immunopotentiators><Immunostimulants><Immunostimulatory drug><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Impaired cognition><Impairment><Incidence><Infection><Inflammation><Inflammatory Response><Injury><Interferon Gamma><Interferon Type II><Interleukin 7 Precursor><Interleukin 7 Precursor Gene><Interleukin-7><Interleukin-7 Gene><Intracellular Communication and Signaling><Investigators><K-Awards><K-Series Research Career Programs><Leukocytes><Leukocytes Reticuloendothelial System><Life><Lymphopoietin-1><Marrow leukocyte><Mediating><Medical><Medication><Memantin><Memantine><Mentors><Methods><Modeling><Modern Man><Molgramostin><Morbidity><Morbidity - disease rate><Multiple Injuries><Multiple Trauma><NIH><National Institutes of Health><Nerve><Nervous System Injuries><Nervous System Trauma><Nervous System damage><Neuraxis><Neurocognitive><Neurologic outcome><Neurological Damage><Neurological Injury><Neurological outcome><Neurological trauma><Nicotinic Acetylcholine Receptors><Nicotinic Receptors><Nosocomial Infections><Outcome><PD-1 antibody><PD1 antibody><Pathway interactions><Patients><Patients with traumatic brain injury><Pharmaceutical Preparations><Pharmacotherapy><Propanolol><Propranolol><Prospective cohort><Rat><Rats Mammals><Rattus><Recovery><Research><Research Career Program><Research Design><Research Personnel><Researchers><Risk><Rodent><Rodentia><Rodents Mammals><Scientist><Secondary to><Signal Transduction><Signal Transduction Systems><Signaling><Study Type><Surgeon><TBI Patients><TC-GM-CSF><Testing><Therapeutic><Time><Training><Translational Research><Translational Science><Trauma><Traumatic Brain Injury><Traumatic injury><Tumor-Cell Human GM Colony-Stimulating Factor><United States National Institutes of Health><Vulnerable Populations><White Blood Cells><White Cell><aPD-1><aPD1><adverse consequence><adverse outcome><antagonism><antagonist><anti programmed cell death 1><anti-PD-1><anti-PD-1 Ab><anti-PD-1 antibodies><anti-PD-1 monoclonal antibodies><anti-PD1><anti-PD1 Ab><anti-PD1 antibodies><anti-PD1 monoclonal antibodies><anti-programmed cell death protein 1><anti-programmed cell death protein 1 antibodies><anti-programmed death-1 antibody><antiPD-1><antiPD1><aspirate><attenuate><attenuates><attenuation><behavior test><behavioral test><beta blocker><beta-Adrenergic Blocking Agents><beta-Adrenergic Receptor Blockaders><biological signal transduction><blood loss><brain damage><brain-injured><career><central nervous system injury><cholinergic><clinical relevance><clinically relevant><cognitive dysfunction><cognitive loss><cohort><controlled cortical impact><critical injury><devastating injury><develop therapy><developmental><disability><drug treatment><drug/agent><education planning><enroll><experience><experiment><experimental research><experimental study><experiments><femoral artery><granulocyte macrophage colony stimulating factor><immune function><immune modulation><immune regulation><immune stimulatory agent><immune stimulatory drug><immune stimulatory therapeutic><immune suppression><immune suppressive activity><immune suppressive function><immunologic reactivity control><immunomodulatory><immunoneurology><immunophenotype><immunoregulation><immunoregulatory><immunostimulatory agents><immunostimulatory biologics><immunosuppressive activity><immunosuppressive function><immunosuppressive response><improved><improved outcome><infection risk><injured><injured CNS><injured child><injured children><injuries><injury in children><institutional infection><intervention development><juvenile><juvenile human><kids><lFN-Gamma><member><model design><model of animal><mortality><neural><neural inflammation><neuroimmunology><neuroinflammation><neuroinflammatory><neurotrauma><pathway><pediatric><pediatric injury><pharmacologic><polytrauma><pre-clinical><preclinical><prevent><preventing><programs><prospective><restoration><severe injury><skills><study design><therapeutic target><therapy development><timeline><tool><translation research><translational investigation><traumatic brain damage><traumatic brain injury patients><treatment development><vulnerable group><vulnerable individual><vulnerable people><white blood cell><white blood corpuscle><youngster><αPD-1><αPD1>