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A mouse model with humanized telomere homeostasis

Award Number: R01AG073423
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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A mouse model with humanized telomere homeostasis - Abstract The goal of this project is to develop a mouse model that acquires human-like telomere homeostasis for the study of human aging, cancer, and other age-related diseases. In humans, most somatic cells lack telomerase expression and cannot replenish their telomeres. Telomeres progressively shorten upon successive cell divisions, functioning as an aging clock. Consequently, telomere attrition is a critical factor of human aging and telomere stabilization, predominantly via telomerase activation, is an essential event in the development of most human cancers. On the other hand, many other organisms, including laboratory mice, do not exhibit telomere-mediated replicative aging. Mice possess long telomeres and ubiquitous telomerase activity in adult tissues. This interspecies difference has become a bottleneck for addressing many fundamental questions in human aging and cancer biology using mouse models. To tackle this challenge, we have started to create a mouse strain with humanized telomere homeostasis. We have engineered a humanized mouse Tert allele (hmTert) by using regulatory sequences from the human TERT gene (hTERT) to replace their mouse counterparts. We found that the hmTert gene regulation recapitulated that of the hTERT gene during mouse development and in mouse adult tissues. Remarkably, the hmTert allele imposed a much shorter telomere length setpoint than the wildtype mTert gene in mice. In this application, we propose three specific aims: 1) Create a mouse strain with hmTert alleles and human-like short telomeres; 2) Study replicative aging in mice with humanized telomere homeostasis; and 3) Determine lifespan and health-span of mice with humanized telomeres.


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 = $438,643 )
2026	2026	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Aging Research	000	5	6/3/2026	NON-COMPETING CONTINUATION	$438,643
														Subtotal = $438,643

Issue Date FY: 2025 ( Subtotal = $490,647 )
2025	2025	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Aging Research	000	4	7/31/2025	NON-COMPETING CONTINUATION	$439,707
2025	2025	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Aging Research	001	4	9/9/2025	SUPPLEMENT FOR EXPANSION	$50,940
														Subtotal = $490,647

Issue Date FY: 2024 ( Subtotal = $451,189 )
2024	2024	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Aging Research	000	3	5/17/2024	NON-COMPETING CONTINUATION	$451,189
														Subtotal = $451,189

Issue Date FY: 2023 ( Subtotal = $452,741 )
2023	2023	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Aging Research	002	2	8/17/2023	NON-COMPETING CONTINUATION	$451,189
2023	2022	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Aging Research	001	1	8/7/2023	NEW	$1,552
2023	2022	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Aging Research	000	1	1/12/2023	NEW	$0
														Subtotal = $452,741

Issue Date FY: 2022 ( Subtotal = $461,767 )
2022	2022	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Aging Research	000	1	9/9/2022	NEW	$461,767
														Subtotal = $461,767

Grand Total All Awards = $2,294,987

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A mouse model with humanized telomere homeostasis

Award Number: R01AG073423

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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