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The role of UBE3A in gliopathic seizures

Award Number: R01NS115776
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: 09/30/2020
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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The role of UBE3A in gliopathic seizures - As many as ~3 million individuals suffer from epileptic seizures in the US alone. Although some forms of epilepsy respond quite well to anti-seizure medications, a substantial portion of individuals suffering from epilepsy do not respond well to medication or dietary treatments. One way to investigate the underlying molecular and cellular pathology of seizure disorder is by studying a genetically defined syndrome where epilepsy is a prominent feature. Approximately 25-50% of individuals with Duplication 15q syndrome (Dup15q) suffer from difficult to control seizures. The prevailing hypotheses to explain seizures in Dup15q are maternal specific neuronal elevation of the ubiquitin E3 ligase UBE3A and/or duplication of a cluster of GABA receptor genes located adjacent to UBE3A at 15q11.2-q13.1. Studies using the fruit fly, Drosophila melanogaster, from our laboratory indicates that these seizures may be caused by elevated levels of UBE3A in glia, not neurons as previously proposed. The premise for this proposal is that seizures are caused by elevated levels of the UBE3A protein in glia, not neurons, providing not only a pathway to molecular mechanism for Dup15q related epilepsy, but also a paradigm shift, directly implicating glial cells in the etiology of seizures. The experiments outlined in this proposal are designed to investigate the developmental timing and molecular changes in glial cells over-expressing Dube3a and to reveal how these changes are recapitulated in a new mouse model we developed that expresses Ube3a in glial cells. Everything we learn from these studies in flies will be directly disseminated to a team of seizure experts who work at the Duplication 15q centers of excellence throughout the country. The identification of new therapeutic targets for Dup15q epilepsy may also provide new treatment options to individuals who are pharmacoresistant to current anti-epileptics.


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	2024	THE ADMINISTRATORS OF TULANE EDUCATIONAL FUND	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	3/14/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$367,677
2025	2024	UNIVERSITY OF TENNESSEE	62 S DUNLAP ST	MEMPHIS	TN	38103	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	3/13/2025	NON-COMPETING CONTINUATION	-$367,677
2025	2024	THE ADMINISTRATORS OF TULANE EDUCATIONAL FUND	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	6	5/13/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$214,965
2025	2024	UNIVERSITY OF TENNESSEE	62 S DUNLAP ST	MEMPHIS	TN	38103	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	5	5/13/2025	NON-COMPETING CONTINUATION	-$1
2025	2023	UNIVERSITY OF TENNESSEE	62 S DUNLAP ST	MEMPHIS	TN	38103	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	4	5/13/2025	NON-COMPETING CONTINUATION	-$214,964
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $367,678 )
2024	2024	UNIVERSITY OF TENNESSEE	62 S DUNLAP ST	MEMPHIS	TN	38103	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	7/25/2024	NON-COMPETING CONTINUATION	$367,678
														Subtotal = $367,678

Issue Date FY: 2023 ( Subtotal = $397,860 )
2023	2023	UNIVERSITY OF TENNESSEE	62 S DUNLAP ST	MEMPHIS	TN	38103	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	7/17/2023	NON-COMPETING CONTINUATION	$397,860
														Subtotal = $397,860

Issue Date FY: 2022 ( Subtotal = $404,130 )
2022	2022	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET STE 103	MEMPHIS	TN	38103	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	8/1/2022	NON-COMPETING CONTINUATION	$404,130
														Subtotal = $404,130

Issue Date FY: 2021 ( Subtotal = $410,400 )
2021	2021	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET STE 103	MEMPHIS	TN	38103	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	7/15/2021	NON-COMPETING CONTINUATION	$410,400
														Subtotal = $410,400

Issue Date FY: 2020 ( Subtotal = $418,384 )
2020	2020	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET STE 103	MEMPHIS	TN	38103	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/18/2020	NEW	$418,384
														Subtotal = $418,384

Grand Total All Awards = $1,998,452

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The role of UBE3A in gliopathic seizures

Award Number: R01NS115776

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: 09/30/2020

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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