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Reversing Skeletal Aging by Restoring Functional Skeletal Stem Cell Diversity

Award Number: R00AG066963
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Reversing Skeletal Aging by Restoring Functional Skeletal Stem Cell Diversity - Advancing age is tightly linked to the increasing global incidence of skeletal diseases. Osteoporosis poses a major public health threat for over 54 million Americans as it is interrelated with high fracture rates. Osteoporosis related hip fractures are invariably associated with significant morbidity and strikingly, a 58% mortality rate in the elderly within the first year of injury. This problem is compounded by a lack of efficient preventive and medical therapies for age-related bone disease free of major side effects. Recent studies have revealed adult stem cell populations within bone that could be potentially targeted as a regenerative source to maintain and restore skeletal health. However, breakthroughs in stem cell based-regenerative strategies have been hampered by the inability to isolate bona fide stem cell populations. Our group has helped delineate highly purified skeletal stem cell (SSC) lineages crucial for maintaining normal bone homeostasis and regeneration following injury. My latest results suggest that aging shifts lineage determination of stem cells triggering altered niche dynamics thereby contributing to a decline of regenerative capacity and providing a rationale that skeletal aging is caused by SSC dysfunction. The initial findings of this proposal provide evidence for the existence of multiple SSC subtypes (SSC diversity) present in limb long bones. Transcriptomic analysis at the single-cell level shows that SSCs undergo aging-induced molecular and compositional changes coinciding with functional heterogeneity. I have identified Wnt1 Inducible Signaling Pathway Protein 2 (Wisp2) that is specifically upregulated in the aged SSC lineage. Wisp2 significantly impairs bone formation when applied to SSC in vitro or fractures of young mice in vivo. Aim1 has determined the role of age-related changes in SSC diversity including the relative proportion of SSC subtypes and their functional heterogeneity to skeletal integrity and will now be completed with spatiotemporal single cell analysis to define anatomical changes of SSCs and their niche cell interactions. In Aim2, I will examine the mechanism of stem cell-based skeletal aging through Wisp2, which I hypothesize, may regulate SSC diversity and heterogeneity. Proposed experiments will also address the age-dependent role of stem cell based epigenetic drift and a potential connection to new concepts of stem cell aging such as adverse clonal skeletogenesis. Importantly, I will determine the unexplored identity of the Wisp2 receptor in SSCs by highly sensitive proximity-dependent labeling to identify targetable pathways involved in SSC-mediated skeletal aging. The guidance and research environment provided by my new host institution for my independent research phase is cutting-edge and highly relevant to the purpose of this proposal allowing implementation of the latest transcriptomic, epigenetic and proteomic methods, including single-cell RNA- and ATAC-sequencing, RNAScope, NanoString single cell imaging and TurboID, to interrogate the proposed aims. These studies will establish a new paradigm for understanding skeletal disease from the perspective of SSC diversity and should facilitate the development of new preventive, diagnostic, and therapeutic approaches to tackle skeletal disorders.


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 = $244,021 )
2025	2025	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Aging Research	001	5	7/16/2025	NON-COMPETING CONTINUATION	$19,921
2025	2025	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Aging Research	000	5	12/12/2024	NON-COMPETING CONTINUATION	$224,100
														Subtotal = $244,021

Issue Date FY: 2024 ( Subtotal = $249,000 )
2024	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Aging Research	001	4	6/11/2024	NON-COMPETING CONTINUATION	$24,899
2024	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Aging Research	000	4	12/26/2023	NON-COMPETING CONTINUATION	$224,101
														Subtotal = $249,000

Issue Date FY: 2023 ( Subtotal = $280,741 )
2023	2023	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Aging Research	000	3	3/31/2023	EXTENSION WITH OR WITHOUT FUNDS	$249,000
2023	2023	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Aging Research	001	3	7/13/2023	EXTENSION WITH OR WITHOUT FUNDS	$31,741
														Subtotal = $280,741

Grand Total All Awards = $773,762

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Reversing Skeletal Aging by Restoring Functional Skeletal Stem Cell Diversity

Award Number: R00AG066963

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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