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Understanding the Etiology of CASK Associated Epileptic Encephalopathy

Award Number: R01NS117698
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: 04/01/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Understanding the Etiology of CASK Associated Epileptic Encephalopathy - PROJECT ABSTRACT Epileptic encephalopathies (EEs) are severe brain disorders of early infantile and childhood age onset characterized by epileptic seizures, abnormal electroencephalogram (EEG), severe cognitive and behavioral impairments that might lead to early death. It is estimated that ~2.9 million Americans live with epilepsy and the mortality rate in people with epilepsy is ~2-3 times higher than the general population. Several genetic mutations associate with EEs including mutations in the X-linked intellectual disability gene CASK that are found in patients with Ohtahara syndrome (OS) and West Syndrome (WS). Constitutive CASK deletion in mammals is incompatible with life and the prognosis of CASK hemizygous male patients remains extremely grim. The precise function of CASK and the potential mechanisms by which CASK mutation produces EE remains obscure. Because the constitutive CASK-/- knockout mice exhibited neonatal lethality, we recently generated a novel mouse model of EE by deleting CASK specifically from the neurons (CASKNKO). We found that CASKNKO mice display severe growth retardation, recurrent tonic spasms, EEG anomalies, and myoclonus beginning postnatal day 17 that leads to death by postnatal day 25. Multiple studies have shown that CASK protein is localized at the mitochondrial membranes. Recently, CASK gene expression was found to be regulated in an NAD+/Sirtuin1 dependent manner in mouse neurons. Moreover, we found that mammalian CASK interacts and co-localizes with mitochondrial proteins, and significantly modulates mitochondrial function and number. Based on the evidences from literature and our findings we hypothesize that CASK plays a role in brain mitochondrial function and metabolism, and is critical for optimum neuronal excitability in vivo. To test this hypothesis, we will examine the brain mitochondrial, metabolic, and electrophysiological functional changes as well as synaptic excitatory/inhibitory balance in the CASKNKO mice. We will further identify the specific domain/s of CASK that interacts with mitochondrial proteins, and determine if SIRT1-dependent mitochondrial biogenesis pathway is dysregulated in the brain of CASKNKO mice. Experiments will be performed before and after the onset of myoclonus to distinguish between a potential cause and consequence relation with the disease. We will also test if pharmacological activation of NAD+/SIRT1 pathway can stimulate mitochondrial biogenesis in the brain and CASK expression in glial cells to rescue EE phenotype in the CASKNKO mice. Success in the proposed project will uncover how loss of neuronal CASK alters mitochondrial and synaptic functions to produce EE. The long-term goal of our project is to use the novel CASKNKO EE mouse model to identify potential disease biomarkers and test therapeutic strategies for clinical intervention.


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 = $334,125 )
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	1/15/2025	NON-COMPETING CONTINUATION	$334,125
2025	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	4	1/22/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$51,371
2025	2023	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	1/22/2025	NON-COMPETING CONTINUATION	-$1
2025	2022	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	1/22/2025	NON-COMPETING CONTINUATION	-$51,370
														Subtotal = $334,125

Issue Date FY: 2024 ( Subtotal = -$6,637 )
2024	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	9/24/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$393,730
2024	2023	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	9/23/2024	NON-COMPETING CONTINUATION	-$400,367
														Subtotal = -$6,637

Issue Date FY: 2023 ( Subtotal = $400,368 )
2023	2023	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	2/2/2023	NON-COMPETING CONTINUATION	$40,036
2023	2023	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	12/29/2022	NON-COMPETING CONTINUATION	$360,332
														Subtotal = $400,368

Issue Date FY: 2022 ( Subtotal = $400,368 )
2022	2022	VIRGINIA POLYTECHNIC INSTITUTE AND STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	3/22/2022	NON-COMPETING CONTINUATION	$40,037
2022	2022	VIRGINIA POLYTECHNIC INSTITUTE AND STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/2/2021	NON-COMPETING CONTINUATION	$360,331
														Subtotal = $400,368

Issue Date FY: 2021 ( Subtotal = $415,368 )
2021	2021	VIRGINIA POLYTECHNIC INSTITUTE AND STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/25/2021	NEW	$415,368
														Subtotal = $415,368

Grand Total All Awards = $1,543,592

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Understanding the Etiology of CASK Associated Epileptic Encephalopathy

Award Number: R01NS117698

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: 04/01/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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