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Novel Strategies for Understanding and Treating Fibrous Dysplasia

Award Number: R01AR081336
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Novel Strategies for Understanding and Treating Fibrous Dysplasia - PROJECT SUMMARY Current treatments for many musculoskeletal disorders are often suboptimal. Understanding the signals controlling skeletal homeostasis and repair is of high relevance, since this knowledge is critical for developing effective therapies for common conditions such as osteoporosis and fractures. In this proposal, we study fibrous dysplasia (FD) as a way to understand the regulators of human bone formation, and test if these pathways could then be used to enhance bone repair. FD accounts for 2.5% of all bone lesions and can occur as part of McCune-Albright Syndrome (MAS). FD is caused by genetic mutations in the GNAS locus, leading to a constitutively active Gs-GPCR protein, hence increasing cAMP levels and causing aberrant cellular signaling. Medical treatments for this disfiguring disorder are sorely lacking. This proposal uses new tools, including mouse models, human induced pluripotent stem cells (iPSCs), skeletal stem/progenitor cells, and advanced genetic strategies, to address the critical knowledge gaps and to find novel therapies for these medically significant conditions. We propose three specific aims: Aim 1: Identify novel compounds that directly target Gsα-regulated cAMP and Wnt production. We previously showed that stopping excess Gs-GPCR pathway activity in mice could dramatically reverse FD-like bone lesions. Using a new artificial intelligence computational approach, we found 71 candidate compounds predicted to selectively bind the GsαR201H protein. Preliminary studies demonstrate that some of these show the desired inhibition of GsαR201H-induced basal cAMP production. This Aim takes our top candidates and further characterizes their ability to block cAMP and Wnt activity, as potential molecular tools for manipulating GNAS. We also test if the lead compounds can reverse existing FD lesions in mouse calvarial cultures. Aim 2: Test if Wnt inhibition can prevent FD bone lesions in mice. How the GNAS mutations in FD cause dramatic bone formation is still poorly defined. We recently found that three proteins, Wnt4, Wnt5a, and Wnt9a, are upregulated in both mouse and human FD bone lesions. This Aim tests if blocking these proteins can reverse FD bone lesions in mice, and examines how each Wnt protein impacts FD lesion pathology. Aim 3: Determine the pathways that are dysregulated in human FD bone lesions and assess the roles of WNT signaling in human skeletal stem/progenitor cells during fracture repair. This aim uses advanced genetics on human FD bone samples to identify the malfunctioning cell types that cause FD. We also test how overactivating WNT4, WNT5a, or WNT9a in human skeletal stem/progenitor cells affect bone formation in a fracture healing model. These results will identify new targets for treating FD and for promoting fracture healing. This application address key knowledge gaps about which Wnt signaling molecules drive FD and how they impact human osteogenesis. The proposal comes from an established, strong, collaborative, multi-institutional team with extensive experience in GPCRs, FD, bone biology, and bone analytical methods. 1


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 = $636,931 )
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	4/27/2026	NON-COMPETING CONTINUATION	$631,007
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	5/7/2026	SUPPLEMENT FOR EXPANSION	$5,924
														Subtotal = $636,931

Issue Date FY: 2025 ( Subtotal = $683,869 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	4/22/2025	NON-COMPETING CONTINUATION	$601,542
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	3	8/29/2025	SUPPLEMENT FOR EXPANSION	$35,542
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	5/7/2025	NON-COMPETING CONTINUATION	$46,785
														Subtotal = $683,869

Issue Date FY: 2024 ( Subtotal = $675,951 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	2	9/18/2024	SUPPLEMENT FOR EXPANSION	$29,618
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	4/10/2024	NON-COMPETING CONTINUATION	$599,690
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	5/31/2024	NON-COMPETING CONTINUATION	$46,643
														Subtotal = $675,951

Issue Date FY: 2023 ( Subtotal = $699,594 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	6/20/2023	NEW	$699,594
														Subtotal = $699,594

Grand Total All Awards = $2,696,345

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Novel Strategies for Understanding and Treating Fibrous Dysplasia

Award Number: R01AR081336

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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