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Brain-invading monocytes promote the deleterious consequences of status epilepticus

Award Number: R01NS112350
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: 12/01/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Brain-invading monocytes promote the deleterious consequences of status epilepticus - Project Summary/Abstract Status epilepticus (SE) is a frequent neurological emergency that can reduce the quality of life of those affected, produce cognitive deficits, and result in the development of epilepsy. Brain inflammation is an invariable feature of seizure activity and is believed to contribute to neuronal demise and exacerbate the deleterious behavioral consequences of unabated seizures. However, the involvement of blood-borne immune cells in the brain's inflammatory reaction after seizures remains unresolved. We have recently identified a subclass of circulating monocytes that invades brain tissue after seizures. Our findings indicate that blocking monocyte infiltration, via Ccr2 knockout, reduces the deleterious consequences of SE. These results prompt us to ask whether brain-invading monocytes are a novel therapeutic target to attenuate the adverse effects of seizures, alleviate cognitive dysfunction, and inhibit the development of epilepsy after SE. My hypothesis is that microglia-driven recruitment of brain-invading monocytes is a strong driver of SE-induced neurobehavioral deficits and epileptogenesis in the weeks following SE because pro-inflammatory monocytes migrate across the BBB promoting albumin extravasation into the brain. The lessons gleaned from completion of the proposed studies will lead to insights into myeloid cell biology in epilepsy as well as brain disease in general. The proposed studies will determine how the peripheral immune system can impact central immune reactions and contribute to co-morbidities, leading to decreased quality of life in individuals afflicted with epilepsy. Utilizing multiple techniques, my specific aims are designed to investigate and validate important components of this hypothesis. Aim 1. To test the hypothesis that brain-infiltrating monocytes engraft in the brain and maintain their own pro-inflammatory profile, exacerbating a pro-inflammatory response in microglia. Aim 2. To test the hypothesis that albumin extravasation is reliant on monocyte migration across the BBB. Aim 3. To determine if blocking monocyte brain entry exerts antiepileptogenic or disease modifying effects after SE. If our aims are achieved, then this would support continued efforts for targeting peripheral monocytes with therapies, which could have a significant impact on reducing the burden of neurological disease, a major mission of NINDS.


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 = $307,125 )
2025	2025	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	11/22/2024	NON-COMPETING CONTINUATION	$307,125
														Subtotal = $307,125

Issue Date FY: 2024 ( Subtotal = $331,013 )
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	4/15/2024	NON-COMPETING CONTINUATION	$23,888
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	12/18/2023	NON-COMPETING CONTINUATION	$307,125
														Subtotal = $331,013

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	5/9/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $341,250 )
2022	2022	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	3/24/2022	NON-COMPETING CONTINUATION	$34,125
2022	2022	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	11/15/2021	NON-COMPETING CONTINUATION	$307,125
														Subtotal = $341,250

Issue Date FY: 2021 ( Subtotal = $341,250 )
2021	2021	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	1/8/2021	NON-COMPETING CONTINUATION	$34,125
2021	2021	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	11/16/2020	NON-COMPETING CONTINUATION	$307,125
														Subtotal = $341,250

Issue Date FY: 2020 ( Subtotal = $341,250 )
2020	2020	EMORY UNIVERSITY	1599 CLIFTON RD.	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/25/2019	NEW	$341,250
														Subtotal = $341,250

Grand Total All Awards = $1,661,888

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Brain-invading monocytes promote the deleterious consequences of status epilepticus

Award Number: R01NS112350

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: 12/01/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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