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Genetic variant-based drug discovery targeting conserved pathways of aging

Award Number: U19AG056278
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2017
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Genetic variant-based drug discovery targeting conserved pathways of aging - ABSTRACT (OVERALL) Aging is the greatest risk factor for most common chronic human diseases and a logical target for developing interventions to prevent, mitigate or reverse multiple age-related morbidities. Over the past two decades, genetic and pharmacologic interventions targeting conserved pathways of growth and metabolism have consistently led to substantial extension of the lifespan and healthspan in model organisms as diverse as nematodes, flies and mice. It is imperative to extend the results obtained with model organisms to aging humans. In this proposed renewal of our U19 project “Genetic variant-based drug discovery targeting conserved pathways of aging” we propose to continue using human centenarians to identify genetic variants as targets for developing drugs that improve human healthy aging. During the first funding period, we identified rare variants and longevity pathways in our centenarian cohort including coding variants in IGF-1R, SIRT6, and ATM, and functional non-coding variants in FOXO3A, SIRT6 and components of the IKK/NF-B pathway, RelA/p65, NFKB1/p50 and NFKB1a (IB). Having established the feasibility of using the genetics of human centenarians to identify genes and pathways as candidates for potential drug targets for promoting human healthspan, the focus of this renewal application will be to expand the program through whole exome analysis of our own, significantly expanded cohort and other centenarian cohorts, further gene functionalization, the use of novel mouse models of accelerated aging to validate the role of the rare variants and pathways in healthy longevity, and expansion of our pipeline of screening for candidate interventions. To accomplish these goals, we propose an interdisciplinary approach, making full use of the latest advances in cellular genomics, high-throughput functional screening, stem cell biology, mouse and human genetics and drug screening. This renewal application is comprised of four projects. Project 1: Genetic analysis of extreme human longevity (Zhang, Dong, and Vijg); Project 2: Identification of functional genetic rare variants (Suh and Yu), Project 3: Validation and characterization of rare variants in mouse models of aging (Niedernhofer) and Project 4: Development of novel therapeutics targeting the identified variants and pathways (Robbins and Gorbunova). There is also one Research Resource Core for Data Integration and Sharing (Core B; Zhang and Dong) as well as an Administrative Core (Core A; Vijg, Robins and Barzilai). We expect that the continued and expanded use of the human centenarian cohorts will allow us to obtain more detailed genetic information critical for identifying targets for the development of drugs for extending human healthspan, for example, by increasing resilience to Alzheimer’s Disease pathology.


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 = $0 )
2025	2024	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	000	8	6/27/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $2,694,643 )
2024	2024	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	006	8	8/5/2024	NON-COMPETING CONTINUATION	$2,694,643
2024	2023	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	000	7	10/24/2023	COMPETING CONTINUATION	$0
2024	2023	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	004	6	2/22/2024	SUPPLEMENT FOR EXPANSION	-$444,098
2024	2023	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	003	7	2/22/2024	COMPETING CONTINUATION	$518,718
2024	2023	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	005	7	5/17/2024	COMPETING CONTINUATION	$0
2024	2021	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	002	6	2/22/2024	NON-COMPETING CONTINUATION	-$74,620
2024	2021	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	001	6	11/22/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,694,643

Issue Date FY: 2023 ( Subtotal = $3,266,581 )
2023	2023	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	000	6	1/25/2023	SUPPLEMENT FOR EXPANSION	$444,098
2023	2023	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	002	7	8/23/2023	COMPETING CONTINUATION	$2,822,483
2023	2023	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	003	6	8/23/2023	SUPPLEMENT FOR EXPANSION	$0
2023	2021	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	001	6	8/23/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $3,266,581

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	000	6	6/25/2022	NON-COMPETING CONTINUATION	$0
2022	2021	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	001	6	8/31/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $1,812,656 )
2021	2021	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	003	6	8/17/2021	NON-COMPETING CONTINUATION	-$47,427
2021	2021	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	000	6	4/29/2021	NON-COMPETING CONTINUATION	$1,812,656
2021	2021	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	001	6	7/16/2021	NON-COMPETING CONTINUATION	$47,427
2021	2020	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	002	5	8/17/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,812,656

Issue Date FY: 2020 ( Subtotal = $2,546,324 )
2020	2020	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	001	5	5/28/2020	NON-COMPETING CONTINUATION	$1,876,472
2020	2020	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	003	5	7/31/2020	SUPPLEMENT FOR EXPANSION	$334,926
2020	2020	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	002	5	7/30/2020	SUPPLEMENT FOR EXPANSION	$334,926
2020	2019	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	000	4	2/7/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,546,324

Issue Date FY: 2019 ( Subtotal = $2,005,861 )
2019	2019	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	006	4	8/2/2019	NON-COMPETING CONTINUATION	$0
2019	2019	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	007	4	8/17/2019	NON-COMPETING CONTINUATION	$0
2019	2019	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	003	4	4/16/2019	NON-COMPETING CONTINUATION	$1,812,559
2019	2019	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	009	4	9/4/2019	SUPPLEMENT FOR EXPANSION	$76,552
2019	2019	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	010	4	9/5/2019	SUPPLEMENT FOR EXPANSION	$116,750
2019	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	005	3	5/13/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$966,925
2019	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	004	2	5/13/2019	NON-COMPETING CONTINUATION	-$966,925
2019	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	002	3	2/12/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$773,955
2019	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	000	2	10/24/2018	NON-COMPETING CONTINUATION	$0
2019	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	008	3	8/18/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2019	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	001	2	2/11/2019	NON-COMPETING CONTINUATION	-$773,955
														Subtotal = $2,005,861

Issue Date FY: 2018 ( Subtotal = $1,816,631 )
2018	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	000	2	6/11/2018	NON-COMPETING CONTINUATION	$1,816,631
														Subtotal = $1,816,631

Issue Date FY: 2017 ( Subtotal = $1,910,686 )
2017	2017	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	000	1	9/15/2017	NEW	$1,910,686
														Subtotal = $1,910,686

Grand Total All Awards = $16,053,382

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Genetic variant-based drug discovery targeting conserved pathways of aging

Award Number: U19AG056278

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/15/2017

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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