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Mechanisms for Improving Cognitive Outcome in Pediatric Epilepsy with ACTH

Award Number: K22NS104230
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/15/2017
PERIOD OF PERFORMANCE END DATE: 11/30/2023

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Mechanisms for Improving Cognitive Outcome in Pediatric Epilepsy with ACTH - Epilepsy, particularly pediatric epilepsy, is associated with a very high incidence of cognitive, behavioral and psychiatric comorbidities that are often more detrimental to overall quality of life than the seizures themselves. Aggressive treatment of seizures has been the gold standard, with the belief that this will also minimize cognitive and psychiatric comorbidities. However, very little focus has been placed on treatment of these comorbidities directly and clinical data suggest that focusing on seizure treatment alone does not effectively treat cognitive impairment. We have recently found that ACTH, an endogenous part of the hypothalamic- pituitary-adrenal axis that is often exogenously administered to children with severe epilepsies, can improve cognitive outcome in rats without altering seizure parameters. While it was previously thought that the primary mechanism of action for ACTH was through the release of corticosteroids, new research suggests that melanocortin 4 receptor (MC4R) activation in neuronal and glial populations is neuroprotective and can improve outcomes in other disease models. We hypothesize that MC4R agonism in the CNS with ACTH is a key mechanism of action by which it can improve cognitive outcomes after early life seizures (ELS). We further hypothesize that early treatment with ACTH will normalized functional organization of neural networks within and between the prefrontal cortex and the hippocampus, and that this improvement will provide a systems-level mechanism underpinning its mechanism of action. Understanding how ACTH can prevent cognitive deficits without altering seizure parameters is crucial for finding novel treatment approaches for these deficits. Therefore, the scientific aims of this study are to: 1) (Phase I) determine the role of MC4R signaling in the brain on subsequent cognition in control animals and (Phase II) ELS animals, 2) (Phase I) determine the effect of early treatment with ACTH on synaptic plasticity in adult neuronal networks in the PFC after ELS and finally 3) (Phase II) determine the effect of early treatment with ACTH on adult neuronal networks in vivo and executive dysfunction associated with ELS. To achieve these goals, I require additional training, both formal through a “Methods in Computational Neuroscience” course at the Marine Biological Laboratory and informal with my co-mentor, Dr. Mahoney, in order to develop the neurocomputational modeling tools necessary for exploring the systems-level mechanisms of cognitive impairment after ELS and the prevention of such impairments with ACTH. The studies proposed are designed to understand the developmental role of ACTH and MC4Rs on cognitive networks in ELS. Successful completion of this project has the potential to change the way we think about treatment of pediatric epilepsy, and may have implications for the treatment of other neurodevelopmental disorders as well.


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 = -$147,707 )
2024	2022	THE NEMOURS FOUNDATION	1600 ROCKLAND RD	WILMINGTON	DE	19803	NEW CASTLE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	4/15/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$147,707
														Subtotal = -$147,707

Issue Date FY: 2022 ( Subtotal = $242,406 )
2022	2022	NEMOURS FOUNDATION, THE	1600 ROCKLAND RD	WILMINGTON	DE	19803	NEW CASTLE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	11/12/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$242,406
2022	2022	NEMOURS FOUNDATION, THE	1600 ROCKLAND RD	WILMINGTON	DE	19803	NEW CASTLE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	5	2/23/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$136,314
2022	2020	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	4	2/23/2022	NON-COMPETING CONTINUATION	-$136,314
2022	2020	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	11/11/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $242,406

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	8/19/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $256,537 )
2020	2020	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	4	8/7/2020	NON-COMPETING CONTINUATION	$256,537
2020	2019	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	2/5/2020	EXTENSION WITH OR WITHOUT FUNDS	$7,391
2020	2018	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/5/2020	NON-COMPETING CONTINUATION	-$7,391
														Subtotal = $256,537

Issue Date FY: 2019 ( Subtotal = $254,210 )
2019	2019	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	8/27/2019	EXTENSION WITH OR WITHOUT FUNDS	$254,210
														Subtotal = $254,210

Issue Date FY: 2018 ( Subtotal = $104,544 )
2018	2018	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	8/20/2018	NON-COMPETING CONTINUATION	$104,544
														Subtotal = $104,544

Issue Date FY: 2017 ( Subtotal = $104,206 )
2017	2017	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/13/2017	NEW	$104,206
														Subtotal = $104,206

Grand Total All Awards = $814,196

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Mechanisms for Improving Cognitive Outcome in Pediatric Epilepsy with ACTH

Award Number: K22NS104230

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/15/2017

PERIOD OF PERFORMANCE END DATE: 11/30/2023

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