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Defining chromostasis - a candidate regulator of healthy aging and longevity

Award Number: R01AG071464
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/11/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Defining chromostasis - a candidate regulator of healthy aging and longevity - PROJECT SUMMARY Chromatin is a key determinant of cell phenotype and function. Therefore, chromatin stability over the lifespan is presumably a pre-requisite for maintenance of cell and tissue phenotype and function, and hence healthy aging and longevity. However, chromatin is not a static fixed structure, but is a dynamic and plastic “breathing” assembly. As a dynamic and plastic entity, chromatin is prone to change or drift, a process likely exacerbated by intrinsic cellular processes and extrinsic/environmental influences. Therefore, this dynamic chromatin likely represents a challenge for a cell to achieve phenotypic stability, healthy aging and longevity, especially for long- lived cells. In other words, given their dynamic chromatin, how do healthy human neurons and cardiomyocytes remain as such for decades? To explain this, we have proposed that cells possess mechanisms of chromatin homeostasis, or chromostasis, that preserve chromatin integrity, suppress phenotypic instability or “plasticity”, and so slow the pace of aging and promote healthy aging. We will test this hypothesis as follows: Specific Aim 1. Test whether altered nucleosome stability affects features of chromostasis and cell phenotypic plasticity. Specific Aim 2. Identify candidate chromostasis genes and small molecule modulators and test their impact on cell phenotypic plasticity. Specific Aim 3. Test whether enhanced chromostasis promotes healthy aging and longevity. This proposal is broadly significant because it will reveal basic mechanisms of physiological chromatin/epigenetic control and how this impinges on healthy aging and longevity, pathological states such as cell transformation, and therapeutic applications such as cell reprogramming. Accordingly, this proposal can have a major impact on scientific understanding and human health by revealing: 1) mechanisms that underlie stable cell phenotype; 2) biomarkers of age-associated degeneration and predisposition to disease; 3) targets for interventions to promote healthy aging, prevent degenerative disease and cancer, and facilitate therapeutic cell reprogramming.


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 = $514,488 )
2024	2024	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	5	5/17/2024	NON-COMPETING CONTINUATION	$514,488
														Subtotal = $514,488

Issue Date FY: 2023 ( Subtotal = $809,706 )
2023	2023	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	4	6/12/2023	NON-COMPETING CONTINUATION	$809,706
														Subtotal = $809,706

Issue Date FY: 2022 ( Subtotal = $840,622 )
2022	2022	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	3	6/29/2022	NON-COMPETING CONTINUATION	$840,622
														Subtotal = $840,622

Issue Date FY: 2021 ( Subtotal = $884,817 )
2021	2021	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	2	6/4/2021	NON-COMPETING CONTINUATION	$884,817
														Subtotal = $884,817

Issue Date FY: 2020 ( Subtotal = $807,699 )
2020	2020	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	1	9/10/2020	NEW	$807,699
2020	2020	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	001	1	9/21/2020	NEW	$0
														Subtotal = $807,699

Grand Total All Awards = $3,857,332

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Defining chromostasis - a candidate regulator of healthy aging and longevity

Award Number: R01AG071464

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/11/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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