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Mechanism and role of mTORC2 in seizure reduction

Award Number: R01NS124145
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: 12/15/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Mechanism and role of mTORC2 in seizure reduction - ABSTRACT Epilepsy is a neurological disorder that poses a major threat to public health and is responsible for an enormous economic and social burden. While some antiepileptic drugs have proven beneficial for the treatment of seizures, they mainly provide symptomatic relief from seizures and often cause serious adverse effects. Thus, the development of novel treatment strategies is of crucial importance. Here we focus on the mammalian target of rapamycin (mTOR), which functions via two distinct complexes mTORC1 and mTORC2, and whose dysfunction has been associated with epilepsy. Based largely on studies utilizing chronic treatment with the drug rapamycin, it is currently believed that hyperactivation of mTORC1 leads to abnormal network rhythmicity associated with epilepsy. However, chronic rapamycin treatment also inhibits the activity of mTORC2. Thus, it remains unclear whether hyperactivation of mTORC1 or mTORC2 leads to the abnormal synchronized neuronal firing during epilepsy. The goal of this new application is to define the mechanism by which activation of mTOR signaling leads to epilepsy, with a special emphasis on mTORC2. In Aim 1, we will use molecular genetics to define the role of mTOR complexes in seizures. In Aim 2, using phosphoproteomics, genetic, pharmacology and in utero electroporation experiments, we will examine the mechanism by which inhibition of mTORC2 reduces seizures. Finally, in Aim 3, we will use a novel selective and efficient inhibitor of mTORC2 and assess its broader therapeutic potential for the suppression of seizures in different models of epilepsy.


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: 2027 ( Subtotal = $0 )
2027	2026	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	10/21/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2026 ( Subtotal = $602,771 )
2026	2026	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/18/2025	NON-COMPETING CONTINUATION	$542,495
2026	2026	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	3/19/2026	NON-COMPETING CONTINUATION	$60,276
														Subtotal = $602,771

Issue Date FY: 2025 ( Subtotal = $542,495 )
2025	2025	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	11/27/2024	NON-COMPETING CONTINUATION	$542,495
														Subtotal = $542,495

Issue Date FY: 2024 ( Subtotal = $584,689 )
2024	2024	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	7/11/2024	NON-COMPETING CONTINUATION	$42,194
2024	2024	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	11/15/2023	NON-COMPETING CONTINUATION	$542,495
2024	2023	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	10/26/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $584,689

Issue Date FY: 2023 ( Subtotal = $549,971 )
2023	2023	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	2/1/2023	NON-COMPETING CONTINUATION	$54,995
2023	2023	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/2/2022	NON-COMPETING CONTINUATION	$494,976
														Subtotal = $549,971

Issue Date FY: 2022 ( Subtotal = $542,051 )
2022	2022	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	8/26/2022	NEW	$0
2022	2022	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/3/2021	NEW	$542,051
														Subtotal = $542,051

Grand Total All Awards = $2,821,977

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Mechanism and role of mTORC2 in seizure reduction

Award Number: R01NS124145

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: 12/15/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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