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Novel mechanisms suppressing the pro-resolving phenotype of peripheral innate immunity following traumatic brain injury

Award Number: R01NS121103
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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ABSTRACT Neuroinflammation has emerged as a critical component of secondary injury and disease progression following brain trauma. Recent pre-clinical studies have shed light on the neurotoxic effects of peripheral innate immunity. Our preliminary findings suggest this overzealous response may be mediated by EphA4/mTOR signaling which negatively regulates the anti-inflammatory state of peripheral-derived monocyte/macrophages (PDMs). The research objective of this application is to characterize the cellular and molecular mechanism(s) underlying innate immunity and PDM polarization status in the regulation of tissue damage and functional recovery following TBI. Our proposal builds upon extensive preliminary and published data demonstrating a distinct protective and reduced pro-inflammatory response in the absence of peripheral EphA4 using chimeric mice following controlled cortical impact (CCI) injury. Interestingly, PDMs-derived from EphA4null mice directly confer neuroprotection and blood brain-barrier preservation in a model of monocyte depletion and replacement. Moreover, we discovered that PDM-specific EphA4 suppresses phosphorylation of key proteins involved in the mTOR pathway, a novel mediator of the pro-resolving state of PDMs. We hypothesize that EphA4 mediates the pro-inflammatory innate immune response by suppressing mTOR signaling, which induces PDM infiltration, polarization and phenotypic behaviors that drive neurovascular dysfunction following TBI. We will employ cell-specific depletions, and PDM replacement as well as novel transgenic murine models. These approaches will include rigorous behavioral, histological and innovative low-input genome-wide epigenomic and transcriptomic assessment of the relevance and mechanism(s) of PDM behaviors. We will also provide a framework for retooling the neuroinflammatory response to accelerate recovery and dampen pro-inflammatory processes after TBI.


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 = $388,000 )
2024	2024	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	4/3/2024	NON-COMPETING CONTINUATION	$388,000
														Subtotal = $388,000

Issue Date FY: 2023 ( Subtotal = $473,745 )
2023	2023	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	4/7/2023	NON-COMPETING CONTINUATION	$400,000
2023	2023	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	5/1/2023	SUPPLEMENT FOR EXPANSION	$73,745
														Subtotal = $473,745

Issue Date FY: 2022 ( Subtotal = $472,041 )
2022	2022	VIRGINIA POLYTECHNIC INSTITUTE AND STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	6/10/2022	SUPPLEMENT FOR EXPANSION	$72,041
2022	2022	VIRGINIA POLYTECHNIC INSTITUTE AND STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	4/8/2022	NON-COMPETING CONTINUATION	$400,000
														Subtotal = $472,041

Issue Date FY: 2021 ( Subtotal = $400,000 )
2021	2021	VIRGINIA POLYTECHNIC INSTITUTE AND STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/24/2021	NEW	$400,000
														Subtotal = $400,000

Grand Total All Awards = $1,733,786

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Novel mechanisms suppressing the pro-resolving phenotype of peripheral innate immunity following traumatic brain injury

Award Number: R01NS121103

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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