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Cell-Specific Actions of IL-1 / IL-1R1 Signaling Following Traumatic Brain Injury

Award Number: R01NS103785
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/15/2018
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Cell-Specific Actions of IL-1 / IL-1R1 Signaling Following Traumatic Brain Injury - ABSTRACT Management of neuroinflammation is a promising target for improving patient outcomes following a traumatic brain injury (TBI), and substantial evidence suggests therapies targeting the interleukin-1 receptor (IL-1R1) pathway may control neuroinflammation. Despite the promise, there have been limited attempts to move anti-interleukin-1 (IL-1) drugs forward for TBI neuroprotection. We hold that a critical reason for the lack of progress on this promising target is the incomplete understanding of the mechanistic underpinnings of IL-1 signaling after a TBI. It is well-recognized that the clinical picture of TBI is a spectrum of different primary injury mechanisms and injury severities, and that it is necessary to understand the secondary injury mechanism as they relate to the primary injury. Over 75% of TBIs are classified as mild. While not all TBIs lead to neurodegeneration, a mild TBI can result in progressive brain atrophy and persistent cognitive dysfunction, and is a known risk factor for the development of Alzheimer’s disease and related dementias. The current knowledge of IL-1 / IL-1R1 signaling after a TBI is almost exclusively following a moderate-to-severe injury. Using our novel genetic mouse models that allow for cell-type regulation of IL-1R1 signaling, and our model of mild TBI caused by a closed head injury (CHI) we will address this fundamental gap in our knowledge by testing the role of IL-1R1 following a mild TBI, and for the first time, define a cellular mechanism for the pathological effects of IL-1R1 following a mild TBI. Importantly our exciting preliminary data has uncovered a critical role for the brain endothelium in regulating neuroinflammation, which is dependent on IL-1R1. Our preliminary results have led us to propose the overall hypothesis: Secondary neuronal injury following a mild TBI is driven by neuroinflammation and vascular dysfunction, which can be reduced through suppression of IL-1R1. The actions of IL-1R1 following a mild TBI will require the involvement of endothelial cells. We will test our hypothesis in the following aims: Aim 1: Assess the role of endothelial IL-1R1 signaling in the neuroinflammatory feedforward loop. Aim 2: Define the role of endothelial IL-1R1 signaling in the vascular response to a CHI. Aim 3: Delineate the role of endothelial IL-1R1 signaling on synaptic plasticity and spatial learning and memory following a CHI. Successful completion of these studies will increase our understanding of the role of IL-1R1 after a mild TBI, and define the role of the brain endothelium in the neuroinflammatory response to a mild TBI. Our results will fill a critical knowledge gap concerning how best to target neuroinflammation to achieve neuroprotection after a mild TBI, and potential for other disease associated with neuroinflammation (i.e., Alzheimer’s disease).


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 = $0 )
2025	2023	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	4/1/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $326,976 )
2023	2023	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	11/30/2022	NON-COMPETING CONTINUATION	$294,279
2023	2023	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	2/2/2023	NON-COMPETING CONTINUATION	$32,697
														Subtotal = $326,976

Issue Date FY: 2022 ( Subtotal = $327,204 )
2022	2022	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	12/14/2021	NON-COMPETING CONTINUATION	$294,482
2022	2022	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	3/28/2022	NON-COMPETING CONTINUATION	$32,722
														Subtotal = $327,204

Issue Date FY: 2021 ( Subtotal = $327,496 )
2021	2021	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	1/26/2021	NON-COMPETING CONTINUATION	$32,751
2021	2021	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	11/23/2020	NON-COMPETING CONTINUATION	$294,745
														Subtotal = $327,496

Issue Date FY: 2020 ( Subtotal = $333,480 )
2020	2020	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/17/2019	NON-COMPETING CONTINUATION	$300,131
2020	2020	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	2/10/2020	NON-COMPETING CONTINUATION	$33,349
														Subtotal = $333,480

Issue Date FY: 2019 ( Subtotal = $333,594 )
2019	2019	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/12/2018	NEW	$333,594
														Subtotal = $333,594

Grand Total All Awards = $1,648,750

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Cell-Specific Actions of IL-1 / IL-1R1 Signaling Following Traumatic Brain Injury

Award Number: R01NS103785

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/15/2018

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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