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Exploring the therapeutic mechanisms of proinflammatory myelin-laden macrophages retention in the injured spinal lesion core

Award Number: R01NS126468
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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Exploring the therapeutic mechanisms of proinflammatory myelin-laden macrophages retention in the injured spinal lesion core - PROJECT SUMMARY Spinal cord injury (SCI) progression can be divided into acute and chronic phases. Following the primary injury, bone marrow-derived macrophages (BMDMɸ) infiltrate to the injured epicenter where they engulf myelin debris to become proinflammatory myelin-laden macrophages (Mye-Mϕ). Mye-Mɸ accumulate in the injured core densely and occupy almost entire epicenter of injured area indefinitely, which would consequently result in: 1) They prevent the entry and growth of axons, which inhibits remyelination. 2) They lose their normal phagocytic capacity for dead cells and cellular debris, which may exacerbate the inflammatory microenvironment. 3) They release inflammatory mediators, which trigger an inflammatory cascade that prevents tissue regeneration. Our data indicated that the migratory potential of BMDMɸ is directly suppressed when they engulf myelin debris. We resently reported that newly formed microvessels and their lining endothelial cells (ECs) in the injured cord are able to engulf myelin debris. Myelin debris engulfment by ECs (Mye-ECs) significantly increased deposition of extracellular matrices (ECM) such as collagen and fibronectin which may serve as extrinsic factor to promote the adhesive interaction between Mye-Mϕ-ECs and lead to Mye-Mϕ retention in the injured lesion. Our central hypothesis is that Mye-Mϕ retention in the injured core is mediated by intrinsic and extrinsic mechanisms which promote Mye-Mɸ retention through ECM adhesion. The objective of the proposed project is to investigate the underlying mechanisms of Mye-Mϕ sequestration and identify treatment strategies that target Mye-Mɸ in the injury site, which may restore normal Mφ functions and lead to improvements in lesion resolution. The rationale for the proposed research is based on preliminary investigations that demonstrate Mye-Mɸ become ‘trapped’ via a mix of intrinsic (Mɸ produced) and extrinsic (environmental) mechanisms within the lesion. Our central hypothesis will be tested in the following specific aims: 1) To study whether myelin debris, either directly or via autocrine pathways, inhibits BMDMϕ migration ability which promotes their lesion retention; 2) To determine whether adhesive ECM produced by Mye-ECs in the injured core aggravates Mye-Mɸ retention; and 3) To investigate whether targeting Mye-Mφ and subsequently switching their phenotype toward a reparative phenotype promotes tissue healing. This research is innovative because we propose that inflammatory Mye- Mɸ trapped within the injured spinal cord lesion contribute to the chronic SCI lesion, preventing full resolution of the injury. This work is significant because Aims 1 and 2 will identify the underlying mechanisms governing Mye-Mφ retention, while Aim 3 will demonstrate novel strategies for the resolution of chronic SCI inflammation and lesions. This will have the positive impact of identifying novel therapeutic strategies for therapeutic interventions not only to treat SCI but also to other demyelinating disorders that generate myelin debris.


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: 2025 ( Subtotal = $340,916 )
2025	2025	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	1/24/2025	NON-COMPETING CONTINUATION	$340,916
														Subtotal = $340,916

Issue Date FY: 2024 ( Subtotal = $367,492 )
2024	2024	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	4/18/2024	NON-COMPETING CONTINUATION	$26,520
2024	2024	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	2/7/2024	NON-COMPETING CONTINUATION	$340,972
														Subtotal = $367,492

Issue Date FY: 2023 ( Subtotal = $378,918 )
2023	2023	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	3/10/2023	NON-COMPETING CONTINUATION	$378,918
														Subtotal = $378,918

Issue Date FY: 2022 ( Subtotal = $378,978 )
2022	2022	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	2/8/2022	NEW	$378,978
														Subtotal = $378,978

Grand Total All Awards = $1,466,304

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Exploring the therapeutic mechanisms of proinflammatory myelin-laden macrophages retention in the injured spinal lesion core

Award Number: R01NS126468

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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