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Evaluating the contribution of senescent cells in a model of post-traumatic epilepsy

Award Number: F30NS143374
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 06/10/2025
PERIOD OF PERFORMANCE END DATE: 10/31/2028

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Evaluating the contribution of senescent cells in a model of post-traumatic epilepsy - Abstract Post-traumatic epilepsy (PTE) is a disorder defined by spontaneous recurrent seizures following a traumatic brain injury (TBI), accounting for ~20% of the 3.5 million cases of epilepsy in the US alone. Currently, no treatment given after a TBI has meaningfully impacted the development of PTE. This may be due to a limited understanding of epileptogenesis, the process by which initial insults lead to chronic seizures. TBI causes DNA damage, inflammation, and impaired synaptic plasticity. Epileptogenesis involves synaptic remodeling, circuit- level changes, and cell death. Excessive inflammation and DNA damage also activate the cellular senescence program, which activates in response to extreme stress or injury. Senescent cells (SCs) are impaired in their normal functions, secrete a host of pro-inflammatory molecules, and are increasingly implicated in age-related diseases. Our group has found that removing SCs halts epileptogenesis in a model of temporal lobe epilepsy, but SCs are unexplored in the context of PTE. The controlled cortical impact (CCI) is an highly reproducible model of TBI in rodents that generates similar pathological features seen in humans. Following a CCI, mice develop memory deficits, sustained neuroinflammation, impaired synaptic plasticity, spontaneous recurrent seizures, and SCs. Recent modifications to the CCI model have dramatically increased the incidence of the seizure phenotype, which was previously variable. I confirmed both the presence of SCs and the high incidence of seizures (63% of mice) in the CCI model. Therefore, I hypothesize that removing SCs will prevent PTE. To test this, I will use a well-characterized SC-ablating drug cocktail (senolytic), dasatinib and quercetin (DQ). I will use DQ in the CCI model of PTE to assess the contribution of SCs in the development of PTE. I will examine the effect of DQ at the cellular (transcriptome sequencing) and system (behavior and seizure incidence) level in order to determine if and how SCs contribute to PTE pathology. By doing so, this study will be the first to evaluate the efficacy of senolytic therapy in this model of PTE, shed light on the mechanisms by which SCs promote epileptogenesis, and provide preclinical data for a novel prophylactic for PTE, an unmet clinical need.


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: 2026 ( Subtotal = $37,414 )
2026	2026	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/26/2026	NON-COMPETING CONTINUATION	$37,414
														Subtotal = $37,414

Issue Date FY: 2025 ( Subtotal = $36,838 )
2025	2025	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	6/5/2025	NEW	$0
2025	2025	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/5/2025	NEW	$36,838
														Subtotal = $36,838

Grand Total All Awards = $74,252

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Evaluating the contribution of senescent cells in a model of post-traumatic epilepsy

Award Number: F30NS143374

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 06/10/2025

PERIOD OF PERFORMANCE END DATE: 10/31/2028

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