L-selectin shedding as a novel therapeutic strategy to mitigate acute secondary damage after spinal cord injury

L-选择素脱落作为减轻脊髓损伤后急性继发性损伤的新治疗策略

• 批准号: 10657545
• 负责人: Dylan A. McCreedy
• 金额: $ 36.6万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657545
• 关键词: Acute; Adhesions; Affect; Antibodies; Attenuated; Behavior; Binding; Blood; Cells; Chemosensitization; Clinical; Contusions; Diclofenac; Disease; Environment; Event; Excision; Exposure to; FDA approved; Goals; Hour; Human; Immune; In Vitro; Individual; Infection; Inflammation; Inflammatory; Injury; Intravenous; Invaded; Knock-in Mouse; L Forms; L-Selectin; Ligand Binding; Ligands; Mediating; Mediator; Modeling; Mus; Myelin; Neurologic Deficit; Neurological outcome; Neutrophil Activation; Non-Steroidal Anti-Inflammatory Agents; Pathogenicity; Patients; Phase; Play; Process; Production; Quality of life; Reactive Oxygen Species; Receptor Signaling; Recovery; Recovery of Function; Recruitment Activity; Rehabilitation therapy; Research; Role; Spinal Cord; Spinal cord injury; Surface; Testing; Therapeutic; Therapeutic Effect; Tissues; Work; adhesion receptor; cell type; central nervous system injury; clinically relevant; cytotoxic; effective therapy; improved; in vitro activity; in vivo; intraperitoneal; intravenous administration; intravenous injection; long term recovery; neurological recovery; neuroprotection; neutrophil; new therapeutic target; novel therapeutic intervention; receptor; recruit; response; response to injury; spinal cord white matter; therapeutic target; white matter

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.

项目总结/文摘