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Promoting regenerative repair of aged cartilage

Award Number: R01AG078609
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/15/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2028
AWARD TERMINATION DATE: 05/05/2025

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Promoting regenerative repair of aged cartilage - PROJECT SUMMARY/ABSTRACT Age is the number one risk factor for osteoarthritis (OA), however, the mechanisms that drive age-associated joint changes and how these contribute to cartilage damage are not well defined. As OA joint tissues age, it is well established that cartilage-forming stem cells (CSCs) display a significant decline in their ability to differentiate, and the joint environment becomes more inflammatory. Both of these factors together undermine the ability to recover from injuries and also contributes to the failure of autologous stem cell therapies. Thus, we propose an innovative dual strategy which will address both. We hypothesize that activation of sirtuin 6 (SIRT6) will rejuvenate older CSCs, and apoptosis signal regulating kinase 1 (ASK1) inhibition will reestablish a regenerative environment in the joint. Together, this novel solution has the potential to greatly augment the ability for CSC differentiation and cartilage repair in the aged population. We will test this hypothesis and determine the epigenetic mechanisms that SIRT6 regulate in the following three Aims. In Aim 1, we will determine the mechanisms by which (a) SIRT6 activation and (b) ASK1 inhibition enhance the cartilage-forming differentiation and pro-survival activities of aged CSCs. In Aim 2, we will determine the efficacy of SIRT6 activation, in the presence of ASK1 inhibition to stimulate cartilage formation in aged, male and female rodents. Finally, in Aim 3, we will determine the efficacy of SIRT6 activation and ASK1 inhibition to promote cartilage regeneration and repair in response to chondral injury in a pre-clinical aged minipig model. These Aims will be achieved through comprehensive in vitro analysis of young and old (male and female) CSCs and macrophages, in proof-of-concept aging rodent models (mice and rats), and a clinically relevant large animal chondral defect model (aged minipig). Importantly, the findings from this proposal are likely to give unique and important insights into the role of epigenetic regulation of aged cells and the role of the surrounding environment in other aging and diseased tissues. If successful, the overall impact of this novel pro-regenerative therapy to ameliorate the ravages of aging and joint injury would represent a significant advancement in the treatment of age-associated diseases, such as OA. Additionally, it will lead to the discovery of new disease-modifying treatments for other organ systems and increase the ability of the aged population to live a healthy, mobile life.


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 = $773,826 )
2026	2026	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Aging Research	000	4	1/22/2026	NON-COMPETING CONTINUATION	$696,444
2026	2026	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Aging Research	001	4	2/25/2026	NON-COMPETING CONTINUATION	$77,382
														Subtotal = $773,826

Issue Date FY: 2025 ( Subtotal = $703,958 )
2025	2025	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Aging Research	000	3	1/17/2025	NON-COMPETING CONTINUATION	$646,492
2025	2025	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Aging Research	002	3	8/11/2025	NON-COMPETING CONTINUATION	$57,466
2025	2024	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Aging Research	001	2	5/5/2025	TERMINATION	$0
														Subtotal = $703,958

Issue Date FY: 2024 ( Subtotal = $748,700 )
2024	2024	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Aging Research	000	2	2/26/2024	NON-COMPETING CONTINUATION	$650,704
2024	2024	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Aging Research	001	2	6/10/2024	NON-COMPETING CONTINUATION	$72,300
2024	2024	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Aging Research	002	2	8/2/2024	SUPPLEMENT FOR EXPANSION	$25,696
														Subtotal = $748,700

Issue Date FY: 2023 ( Subtotal = $737,004 )
2023	2023	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Aging Research	000	1	5/12/2023	NEW	$737,004
														Subtotal = $737,004

Grand Total All Awards = $2,963,488

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Promoting regenerative repair of aged cartilage

Award Number: R01AG078609

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/15/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2028

AWARD TERMINATION DATE: 05/05/2025

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