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Molecular mechanisms of gamma-secretase modulation central to Alzheimer’s disease

Award Number: R01AG080684
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Molecular mechanisms of gamma-secretase modulation central to Alzheimer’s disease - Alzheimer’s disease (AD), a progressive neurodegenerative disease and leading cause of dementia, exacts a tremendous toll on both the healthcare system and society broadly. Although the pathogenesis of AD is poorly understood, it centers on the production of so-called β-amyloid (Aβ) peptides, which are produced from amyloid precursor protein (APP) by the intramembrane protease γ-secretase. Indeed, mutations in the catalytic subunit of γ-secretase alter Aβ production profile and cause familial AD, making the protease a promising target for developing therapies to treat or prevent Alzheimer’s Disease. Specifically, developing agents that can modify γ- secretase activity to selectively reduce the formation of pathogenic β-amyloid species without affecting γ- secretase’s overall activity represent an attractive strategy to target AD. Despite significant progress in studying γ-secretase, we still do not understand how its catalytic activity and specificity are modulated at a mechanistic level. In the proposed project, we will apply a new approach and leverage novel reagents to investigate γ- secretase and its modulation. Using an interdisciplinary approach, we aim to elucidate how the cellular context and external factors modulate γ-secretase at the molecular level. We will also characterize new tools and reagents for γ-secretase and define their mechanism of actions. Collectively, the proposed studies will provide much needed insights into γ-secretase modulation and offer a molecular basis for Alzheimer’s disease pathogenesis and therapeutic development.


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 = $718,002 )
2026	2026	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Aging Research	000	4	12/3/2025	NON-COMPETING CONTINUATION	$718,002
														Subtotal = $718,002

Issue Date FY: 2025 ( Subtotal = $787,877 )
2025	2025	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Aging Research	001	3	8/11/2025	NON-COMPETING CONTINUATION	$64,317
2025	2025	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Aging Research	000	3	11/15/2024	NON-COMPETING CONTINUATION	$723,560
														Subtotal = $787,877

Issue Date FY: 2024 ( Subtotal = $810,132 )
2024	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Aging Research	000	2	11/10/2023	NON-COMPETING CONTINUATION	$729,119
2024	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Aging Research	001	2	5/1/2024	NON-COMPETING CONTINUATION	$81,013
														Subtotal = $810,132

Issue Date FY: 2023 ( Subtotal = $837,184 )
2023	2023	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Aging Research	000	1	11/22/2022	NEW	$837,184
														Subtotal = $837,184

Grand Total All Awards = $3,153,195

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Molecular mechanisms of gamma-secretase modulation central to Alzheimer’s disease

Award Number: R01AG080684

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/01/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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