Document text
Principal Investigator: Dylan A. McCreedy
Organization: TEXAS A&M UNIVERSITY
Fiscal Year: 2024
Award: $46,078
Funding agency: National Institute of Neurological Disorders and Stroke
Project Summary/Abstract
Inflammation plays a critical role in secondary tissue damage after spinal cord injury (SCI), however, there is no
widely accepted therapeutic for mitigating destructive inflammatory events in the injured spinal cord. L-selectin
is an adhesion and signaling receptor on immune cells that has been recently shown to be a critical mediator of
long-term neurological deficits following SCI. Disrupting L-selectin function with diclofenac, an FDA-approved
non-steroidal anti-inflammatory drug (NSAID) that induces L-selectin “shedding”, improves tissue sparing and
long-term recovery when administered by 3 hours post-SCI. L-selectin shedding, therefore, represents a
potential therapeutic strategy to mitigate damage associated with acute inflammation. However, the specific
mechanisms through which L-selectin attenuates secondary tissue damage remain unclear. L-selectin has been
shown to promote destructive effector functions in neutrophils, the most abundant immune cell type in human
blood and first to invade the injured spinal cord in large numbers. The hypothesis of this proposal is that L-
selectin shedding reduces the pathogenic activities of neutrophils and associated secondary tissue
damage after SCI. The objectives of this work are to determine the effect of L-selectin shedding on the activation
of neutrophil effector functions, further elucidate the role of neutrophils in secondary tissue damage after SCI,
and determine if intravenous delivery extends the therapeutic window for diclofenac. Specific Aim 1 will test the
hypothesis that L-selectin shedding reduces the activation of cytotoxic neutrophil effector functions in the
presence of myelin. Myelin can serve as an abundant ligand for L-selectin and may exacerbate cytotoxic effector
functions in neutrophils. Using mice that cannot shed L-selectin (L(E) mice) and WT mice treated with diclofenac,
the effect of L-selectin shedding on neutrophil effector functions will be quantified in vitro in response to myelin
exposure as well as in the acutely injured spinal cord. Specific Aim 2 will test the hypothesis that neutrophils are
the primary immune cell type whose destructive functions are mitigated by L-selectin shedding. Early neutrophil
depletion will be investigated in L(E) mice and in WT mice treated with diclofenac to determine the extent to
which L-selectin shedding reduces secondary damage and neurological deficits by attenuating pathogenic
neutrophil activities. Specific Aim 3 will test the hypothesis that intravenous delivery of diclofenac can induce
rapid shedding of L-selectin on neutrophils in the blood and extend the window of opportunity. Long-term
neurological recovery and tissue sparing will be assessed following delayed intravenous administration of
diclofenac in WT mice. Diclofenac treatment will also be assessed in L(E) mice to confirm that the therapeutic
mechanisms of action is through L-selectin shedding. The collective results will help uncover the roles of L-
selectin shedding and neutrophils in secondary damage after SCI and validate L-selectin shedding as a
therapeutic target to improve long-term neurological recovery. The findings from this proposal will also be
applicable to attenuating damaging inflammation observed in other central nervous system injuries or disorders.
Terms: <Abscission><Active Oxygen><Acute><Adhesions><Affect><Antibodies><Attenuated><Behavior><Binding><Blood><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Blood Reticuloendothelial System><Body Tissues><Bruise><CD62L Antigens><CNS Injury><Cell Body><Cells><Chemosensitization><Chemosensitization/Potentiation><Clinical><Contusions><Dichlofenal><Diclofenac><Dicrofenac><Disease><Disorder><Environment><Event><Excision><Exposure to><Extirpation><FDA approved><Goals><Hour><Human><Immune><Immunes><In Vitro><Individual><Infection><Inflammation><Inflammatory><Injury><Intravenous><Invaded><KI mice><Knock-in Mouse><L Forms><L-Selectin><LAM-1><LAM-1 Leukocyte Adhesion Molecule><LECAM-1><Leu-8 Antigen><Ligand Binding><Ligands><Lymphocyte Adhesion Molecule 1><Marrow Neutrophil><Mediating><Mediator><Medical Rehabilitation><Medulla Spinalis><Mel-14 Antigen><Mice><Mice Mammals><Modeling><Modern Man><Molecular Interaction><Murine><Mus><Myelin><NSAIDs><Neurologic Deficit><Neurologic outcome><Neurological outcome><Neutrophil Activation><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Non-Steroidal Anti-Inflammatory Agents><Oxygen Radicals><Pathogenicity><Patients><Phase><Play><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Potentiation><Pro-Oxidants><Process><Production><QOL><Quality of life><Reactive Oxygen Species><Receptor Protein><Receptor Signaling><Recovery><Recovery of Function><Recruitment Activity><Rehabilitation><Rehabilitation therapy><Removal><Research><Role><Spinal Cord><Spinal Cord Trauma><Spinal Trauma><Spinal cord injured><Spinal cord injury><Surface><Surgical Removal><TQ1 Antigen><Testing><Therapeutic><Therapeutic Effect><Tissues><Traumatic Myelopathy><Voltaren><Work><active recruitment><adhesion receptor><attenuate><attenuates><cell type><central nervous system injury><clinical relevance><clinically relevant><cytotoxic><effective therapy><effective treatment><functional recovery><improved><in vitro activity><in vivo><injured CNS><injuries><injury response><intraperitoneal><intravenous administration><intravenous injection><knockin mice><long term recovery><neurological recovery><neuroprotection><neuroprotective><neutrophil><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><non-steroidal anti-inflammatory drugs><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><receptor><recruit><rehab therapy><rehabilitative><rehabilitative therapy><resection><response><response to injury><social role><spinal cord white matter><substantia alba><therapeutic target><white matter>