Wednesday, December 31, 2025 12/31/2025

Probing mechanisms of long QT type 2-associated neuronal dysfunction using gene-edited stem cell-derived neurons

Award Number: R21NS136833
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: 12/01/2024
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Probing mechanisms of long QT type 2-associated neuronal dysfunction using gene-edited stem cell-derived neurons - The overall objective of this proposal is to investigate cellular mechanisms by which long QT syndrome- associated KCNH2 variants disrupt neuronal function. hERG1, encoded by KCNH2, is a developmentally- regulated potassium channel that mediates cellular excitability. In the heart, loss-of-function KCNH2 variants cause the cardiac disorder long QT syndrome type 2 (LQTS2), and dramatically increase the likelihood of cardiac arrhythmia and sudden cardiac death. KCNH2 is also expressed in the human brain, but the mechanistic impact of KCNH2 variants on neuronal physiology has not been studied. Clinical data show that LQTS2 patients carrying KCNH2 variants develop epilepsy at five times the rate of any other LQTS-associated genes. Further, KCNH2 variants are enriched in cases of sudden unexplained death in epilepsy (SUDEP). How KCNH2 variants predispose LQTS patients to epilepsy and SUDEP has not been explored. There is therefore a critical unmet clinical need to define the mechanistic link between hERG1 potassium channel dysfunction and neuronal hyperexcitability. Here, we will use neurons differentiated from gene-edited and patient-derived human stem cells to determine molecular and cellular mechanisms by which LQTS2-associated KCNH2 variants alter neuronal function. This project will explore the confluence of cardiac and neuronal electrical activity and will provide the foundation for future R01 level-funding.


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 = $234,000 )
2026	2026	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/17/2025	NON-COMPETING CONTINUATION	$234,000
														Subtotal = $234,000

Issue Date FY: 2025 ( Subtotal = $195,000 )
2025	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/29/2024	NEW	$195,000
														Subtotal = $195,000

Grand Total All Awards = $429,000

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Probing mechanisms of long QT type 2-associated neuronal dysfunction using gene-edited stem cell-derived neurons

Award Number: R21NS136833

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: 12/01/2024

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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