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Principal Investigator: Karin Swartz
Organization: CLEMENT J. ZABLOCKI VA MEDICAL CENTER
Fiscal Year: 2024
Funding agency: Veterans Affairs
The objective of this proposal is to decipher the mechanistic role of the pro-inflammatory cytokine IL-12 and its
downstream effector molecules in mediating cytotoxicity and inflammation after spinal cord injury (SCI), a severe
condition with devastating consequences for the neurological function and overall health of affected persons.
Despite some beneficial inflammatory effects on tissue preservation after SCI, excessive and prolonged
inflammation in the injured spinal cord has emerged as a crucial mediator of secondary tissue damage,
significantly expanding the tissue loss beyond that created by the initial trauma. Paradoxically, SCI also causes
systemic immunosuppression, with resultant high risk of life-threatening infections like pneumonia, making it a
crucial task to target the detrimental intraparenchymal inflammation within the spinal cord, without interfering
with beneficial immune reactions both in the spinal cord parenchyma and systemically.
We have previously shown that IL-12 leads to significantly impaired locomotor recovery and tissue
damage after SCI. IL-12 and its receptors are predominantly expressed on astrocytes after SCI. However, the
mechanism of IL-12-mediated tissue damage, if directly via cytotoxic effector molecules or indirectly by regulating
the inflammatory response, is currently unknown. This information is of high importance for the development of
future therapeutic approaches.
We hypothesize that IL-12 signaling originating in astrocytes promotes secondary tissue damage
resulting in functional impairment. We designed the following three aims to address this hypothesis: (i) We will
determine if cell-specific deletion of IL-12 signaling in astrocytes or microglia improves functional locomotor
recovery and reduced autonomic impairment. This will provide information about the cell types initiating IL-12
mediated tissue damage. (ii) We will then determine the effect of specific, local inhibition of STAT1 and STAT4,
known signaling factors of downstream IL-12 effector functions. We will determine the effect of blocking these
specific signals, using well-established techniques of intraspinal injection of AAV-driven shRNA, followed by SCI,
and determination of tissue preservation and the inflammatory response, using cell-specific transcriptomic and
spatial profiling approaches. Finally, we will (iii) assess the functional impact of STAT1 and STAT4 on locomotor
and autonomic recovery.
In summary, this proposal will provide valuable insights into the mechanism of pro-inflammatory cytokine
function after SCI. It can contribute to developing novel therapeutic approaches in the future with the goal to
reduce tissue damage and improve function. This project has high significance for the active military population,
veterans, and civilians, given the incidence of spine trauma and SCI, and the immense potential in targeting
inflammation for mitigating secondary damage after SCI to improve functional outcomes, health, and quality of
life.
Terms: <Address><Affect><Armed Forces Personnel><Astrocytes><Astrocytus><Astroglia><Autonomic Dysfunction><Basal Transcription Factor><Basal transcription factor genes><Body Tissues><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cre Lox technology><Cre LoxP system><Cre lox recombination><Cre lox recombination system><Cre lox system><Cre recombinase/LoxP technology><Cre system><Data><Development><Down-Regulation><Early treatment><Edodekin Alfa><Functional impairment><Future><General Transcription Factor Gene><General Transcription Factors><Genes><Goals><Health><Health Benefit><Histology><Hortega cell><IL-12><IL-12 receptor><IL-12R><IL-23><IL12><IL12RB2><IL12RB2 gene><Immune reaction><Immune response><Immunological response><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Impairment><Incidence><Individual><Infection><Inflammation><Inflammatory><Inflammatory Response><Injury><Interleukin-12><Interruption><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Intraspinal Injections><Laboratories><Life><Locomotor Recovery><Lytotoxicity><Mechanics><Mediating><Mediator><Medulla Spinalis><Mice><Mice Mammals><Microglia><Military><Military Personnel><Modeling><Modernization><Murine><Mus><NKSF><Natural Killer Cell Stimulatory Factor><Nervous System Physiology><Neurologic function><Neurological function><Non-Polyadenylated RNA><Pathogenicity><Pathway interactions><Peripheral><Persons><Pneumonia><Population><Process><Proteins><QOL><Quality of life><RNA><RNA Gene Products><Reaction><Receptor Protein><Recovery><Recovery of Function><Ribonucleic Acid><Risk><Role><SCI Patients><STAT1><STAT1 gene><STAT4><STAT4 gene><STAT91><Secondary to><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Molecule><Site><Soldier><Specificity><Spinal Cord><Spinal Cord Trauma><Spinal Injections><Spinal Trauma><Spinal cord injured><Spinal cord injury><Spinal cord injury patients><Symptoms><Techniques><Testing><Therapeutic><Therapeutic Intervention><Thoracic Portion of Spinal Cord><Thoracic Spinal Cord><Thoracic spinal cord structure><Tissue Expansion><Tissue Preservation><Tissues><Transcription Factor Proto-Oncogene><Transcription factor genes><Trauma><Traumatic Myelopathy><Veterans><astrocytic glia><biological signal transduction><cell type><combat arena><combat operations><combat situation><combat zone><compare to control><comparison control><critical injury><cytokine><cytotoxic><cytotoxicity><design><designing><determine efficacy><devastating injury><developmental><early therapy><effective therapy><effective treatment><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><evaluate efficacy><examine efficacy><functional improvement><functional recovery><gitter cell><high risk><host response><immune suppression><immune suppressive activity><immune suppressive function><immune system response><immunoreaction><immunoresponse><immunosuppressed><immunosuppressive activity><immunosuppressive function><immunosuppressive response><improve function><improved><improved functional outcomes><inflammation marker><inflammatory marker><inhibitor><injuries><insight><interleukin-12 receptor><interleukin-23><intervention therapy><interventional strategy><mechanic><mechanical><mesoglia><microglial cell><microgliocyte><military population><military veteran><nervous system function><neuroprotection><neuroprotective><new drug target><new druggable target><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapy approach><novel therapy target><pathway><perivascular glial cell><pre-clinical study><preclinical study><preservation><receptor><receptor expression><severe injury><shRNA><short hairpin RNA><small hairpin RNA><social role><systemic inflammation><systemic inflammatory response><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic target><transcription factor><transcriptomics><veteran population>