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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)

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PROJECT SUMMARY/ABSTRACT (ADMINISTRATIVE SUPPLEMENT) Aging is the most important risk factor for common human diseases, such as diabetes, cardiovascular disease, and cancer. Hence, targeting basic mechanisms of aging rather than individual diseases is a rational strategy to develop treatments of age-related multi-morbidity. To test the validity of this approach investigators in this U19 leverage the human centenarian resource at the Albert Einstein College of Medicine to identify rare genetic variants associated with extreme human longevity to identify potential drug targets for promoting healthy aging. Using resequencing data of 400 candidate genes in 450 centenarians and 550 controls we identified, in the previous funding period, rare, functional genetic variants and associated pathways enriched in centenarians and potentially important for healthy longevity, including IGF-1, SIRT6, FOXO3A, NF-kB and SMAD3. Importantly, analysis of new, whole exome sequences of 555 centenarians and 508 controls, provided additional candidate variants, e.g., BLM, USP35, UBE3C. A number of the rare variant candidates were further characterized and evaluated functionally in human ES cells and differentiated lineages. We also generated mouse models of some of the variants for analysis of phenotypes relevant for late-life human health and subsequently used the ES cell and mouse model results as leads for developing assays and testing small molecules targeting the pathways affected by these rare variants. Interestingly, many of the rare variants and/or affected pathways could be linked to the DNA damage response, including cellular senescence. Based on the demonstrated success of our approach we now have expanded our whole exome-sequenced cohort to increase robustness of the analysis, identify additional variants and study candidate pathways through RNA-seq, functionalize additional candidate variants in ESCs and generate more mouse models. This should allow us to greatly extend the number of validated therapeutic targets for drug 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: 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	005	7	5/17/2024	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	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	003	7	2/22/2024	COMPETING CONTINUATION	$518,718
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	003	6	8/23/2023	SUPPLEMENT FOR EXPANSION	$0
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	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	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	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	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	002	5	7/30/2020	SUPPLEMENT FOR EXPANSION	$334,926
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	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	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	010	4	9/5/2019	SUPPLEMENT FOR EXPANSION	$116,750
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	009	4	9/4/2019	SUPPLEMENT FOR EXPANSION	$76,552
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	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
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
														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)

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