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Resilience pathways modeling human longevity-promoting ApoE variants in induced pluripotent stem cells

Award Number: R01AG061879
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2018
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Resilience pathways modeling human longevity-promoting ApoE variants in induced pluripotent stem cells - PROJECT SUMMARY Isoforms of ApoE modify the risk for developing Alzheimer’s disease (AD) or cardiovascular disease, and are also associated with exceptional longevity. Specifically, the e2/e2 genotype is associated with exceptional longevity while the e4 allele is negatively associated with longevity. The e4 variant of the ApoE gene is also a major risk factor for AD and is associated with higher levels of Ab deposition in the brain. Correspondingly, the ApoE e2 allele is associated with a lower risk of AD-related neurodegeneration. The mechanisms modulating extended lifespan mediated by e2 compared to e3 and e4 genotypes are not clear. One hypothesis is that the ApoE e2 allele is neuroprotective and compensates for neuronal dysfunction induced by misfolded protein expression in aging and disease. In addition, the developmental program for the ApoE e2 allele may be distinct from the ApoE e4 allele. This is based on a body of literature that suggests the ApoE genotypes effect brain structure and gene expression beginning prenatal development and continuing into late life. Our proposed studies will utilize isogenic induced pluripotent stem cells (iPSCs) engineered with CRISPR/Cas9 to express the three isoforms of the ApoE protein (E2, E3 and E4). Using genetic engineering in preliminary studies, we generated lines carrying e2/e2, e3/e3 and e4/e4 genotypes in control iPSCs and Huntington’s Disease-HD-iPSCs. Recent advances in stem cell research suggest that iPSCs may provide novel models of aging and diseases. We will investigate using stem cell models the role of the exceptional longevity factor ApoE2 in aging and disease with the following Specific Aims: Specific Aim 1. We will characterize the cellular and functional differences in isogenic iPSCs with e2/e2, e3/e3 and e4/e4 genotypes using a systems biology approach. Specific Aim 2: To determine whether longevity-promoting ApoE variants enhance stress resistance and survival and identify the pathways relevant to the neuroprotective effects of the various variants. Specific Aim 3. We will determine if expression of ApoE2 or factors produced by ApoE cells provide increased health span in aged mice. Overall, our approach synergizes a number of unique methodologies to determine how naturally occurring genetic variants associated with Alzheimer’s disease modulate health span in multiple tissues and potentially lifespan. Successful completion of our proposed studies may reveal mechanisms with potential therapeutic exploitation for age-related disease and aging.


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 = $0 )
2026	2022	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	000	5	12/2/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	000	5	6/13/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $879,592 )
2022	2022	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	000	5	7/7/2022	NON-COMPETING CONTINUATION	$879,592
														Subtotal = $879,592

Issue Date FY: 2021 ( Subtotal = $879,592 )
2021	2021	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	000	4	6/3/2021	NON-COMPETING CONTINUATION	$879,592
														Subtotal = $879,592

Issue Date FY: 2020 ( Subtotal = $879,592 )
2020	2020	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	000	3	5/29/2020	NON-COMPETING CONTINUATION	$879,592
														Subtotal = $879,592

Issue Date FY: 2019 ( Subtotal = $879,592 )
2019	2019	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	001	2	5/7/2019	NON-COMPETING CONTINUATION	$879,592
2019	2018	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	000	1	11/2/2018	NEW	$0
														Subtotal = $879,592

Issue Date FY: 2018 ( Subtotal = $879,592 )
2018	2018	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	000	1	9/18/2018	NEW	$879,592
														Subtotal = $879,592

Grand Total All Awards = $4,397,960

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Resilience pathways modeling human longevity-promoting ApoE variants in induced pluripotent stem cells

Award Number: R01AG061879

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/30/2018

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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