Thursday, November 21, 2024 11/21/2024

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

Award Number: R01NS122961
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $400,475 )
2024	2024	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	7/12/2024	SUPPLEMENT FOR EXPANSION	$46,078
2024	2024	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	7/9/2024	NON-COMPETING CONTINUATION	$354,397
														Subtotal = $400,475

Issue Date FY: 2023 ( Subtotal = $463,865 )
2023	2023	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	6/16/2023	SUPPLEMENT FOR EXPANSION	$72,024
2023	2023	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	6/15/2023	NON-COMPETING CONTINUATION	$365,995
2023	2023	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/30/2023	SUPPLEMENT FOR EXPANSION	$25,846
														Subtotal = $463,865

Issue Date FY: 2022 ( Subtotal = $367,537 )
2022	2022	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	7/1/2022	NON-COMPETING CONTINUATION	$367,537
														Subtotal = $367,537

Issue Date FY: 2021 ( Subtotal = $368,071 )
2021	2021	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/23/2021	NEW	$368,071
														Subtotal = $368,071

Grand Total All Awards = $1,599,948

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

Award Number: R01NS122961

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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