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Progressive states of cell-cycle withdrawal

Award Number: R01AG082942
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Progressive states of cell-cycle withdrawal - Project Summary Senescence is the process by which a cell permanently stops proliferating due to cellular aging or damage but does not die. Induction of senescence is often desirable during cancer treatment to prevent the proliferation of aberrant cells, but it also impedes cellular function and regenerative capacity as we age. The study of cellular senescence is hindered by the fact that senescence is difficult to distinguish from other states of cell-cycle withdrawal such as quiescence, a transient cellular resting state. This is because quiescence and senescence are defined by overlapping molecular markers and because these cell-cycle transitions occur heterogeneously from cell to cell. Despite obvious medical relevance, it is unclear whether senescence and quiescence are truly distinct states. Here we propose to test the hypothesis that senescence and quiescence exist on a continuum of cell-cycle withdrawal where the probability of cell-cycle re-entry steadily declines toward zero as cells become senescent. We will leverage our unique expertise in long-term, time-lapse microscopy, automated single- cell tracking, and the development of sensors for cell-cycle progression and cell-cycle withdrawal to unveil gradations of cell-cycle withdrawal that are invisible by standard bulk approaches. Our specific aims are 1) To determine the predictive power of prevailing senescence markers as binary markers of senescence and as graded markers of quiescence depth, 2) To determine at the transcriptomic level whether quiescence and senescence are distinct states or part of a continuum of cell-cycle withdrawal, and 3) To the identify the DNA damage and telomere features that predict permanent cell-cycle withdrawal as cells age toward replicative senescence. If successful, this work will improve our ability to define molecularly the state of senescence and will generate new fundamental knowledge about the onset of senescence. Our work could improve the ability to predict tumor relapse after cancer therapy, help quantify a cell’s physiological age and reproductive potential, identify ways to rejuvenate aged cells, and improve the safety of senolytic drugs that eliminate senescent cells.


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 = $370,740 )
2025	2025	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Aging Research	001	3	6/13/2025	NON-COMPETING CONTINUATION	$30,264
2025	2025	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Aging Research	000	3	4/3/2025	NON-COMPETING CONTINUATION	$340,476
														Subtotal = $370,740

Issue Date FY: 2024 ( Subtotal = $394,713 )
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Aging Research	000	2	4/25/2024	NON-COMPETING CONTINUATION	$394,713
														Subtotal = $394,713

Issue Date FY: 2023 ( Subtotal = $349,636 )
2023	2023	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Aging Research	000	1	9/21/2023	NEW	$349,636
														Subtotal = $349,636

Grand Total All Awards = $1,115,089

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Progressive states of cell-cycle withdrawal

Award Number: R01AG082942

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/30/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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