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Leveraging genetically-encoded heterogeneity to understand TANDs and seizures in novel models of TSC

Award Number: R01NS134491
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: 02/16/2024
PERIOD OF PERFORMANCE END DATE: 11/30/2028

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Leveraging genetically-encoded heterogeneity to understand TANDs and seizures in novel models of TSC - Project Summary The long-term goal of this project is to understand the mechanisms that underlie the neurological consequences of Tuberous Sclerosis Complex (TSC). TSC is a profoundly complex genetic disorder caused by mutations in either the TSC1 or TSC2 gene and characterized by benign tumor growth in multiple systems in the body. TSC is associated with epilepsy in up to 90% of patients that is often refractory to surgical or targeted pharmacological intervention. In addition to seizures, TSC-associated neurological disorders (TANDs) are present in up to 85% and intellectual disability is present in up to 70% of patients. Interestingly, single TSC1 or TSC2 mutations can have differential effects between affected individuals, and even identical inherited variants can result in different disease profiles. This indicates significant heterogeneity in patient outcomes, the mechanisms for which is currently unknown; understanding the mechanism for this difference in prognosis will allow us to identify novel therapeutic approaches capable of modifying outcome in TSC. We recently developed and validated a model system of this heterogeneity to improve our ability to probe the basic biology of TSC and explore the neural network differences underlying seizures and TANDs. Our novel mice have a germline Tsc1 heterozygous knockout which, when introduced to controlled genetic background diversity, faithfully recapitulate patient heterogeneity in TSC outcomes with the clinically relevant gene dosage and expression pattern. We have remarkable preliminary data showing that the same Tsc1 haploinsufficiency results in a spectrum of background-dependent differences in TSC outcomes. This spectrum allows us to explore how networks underlying cognition and seizure are differentially affected by the same precipitating genetic insult. We hypothesize that genetic background-associated differences in seizure and TANDs outcomes resulting from Tsc1 haploinsufficiency will manifest as changes in neuronal dynamics, partially mediated by aberrant astrocyte modulation of these neuronal dynamics. We will test this hypothesis with the following aims: 1) Phenotype the repertoire of behavioral impairments in Tsc1 haploinsufficient mice, 2) Characterize the relationship between changes in neuronal dynamics, seizure and TANDs, 3) Describe changes in excitatory/inhibitory dynamics and explore the role of non-neuronal populations in changes in E/I balance that underlie 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: 2026 ( Subtotal = $316,617 )
2026	2026	THE NEMOURS FOUNDATION	1600 ROCKLAND RD	WILMINGTON	DE	19803	NEW CASTLE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	12/16/2025	NON-COMPETING CONTINUATION	$316,617
														Subtotal = $316,617

Issue Date FY: 2025 ( Subtotal = $317,858 )
2025	2025	THE NEMOURS FOUNDATION	1600 ROCKLAND RD	WILMINGTON	DE	19803	NEW CASTLE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	11/22/2024	NON-COMPETING CONTINUATION	$317,858
														Subtotal = $317,858

Issue Date FY: 2024 ( Subtotal = $361,645 )
2024	2024	THE NEMOURS FOUNDATION	1600 ROCKLAND RD	WILMINGTON	DE	19803	NEW CASTLE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	2/15/2024	NEW	$361,645
														Subtotal = $361,645

Grand Total All Awards = $996,120

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Leveraging genetically-encoded heterogeneity to understand TANDs and seizures in novel models of TSC

Award Number: R01NS134491

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: 02/16/2024

PERIOD OF PERFORMANCE END DATE: 11/30/2028

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