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Elucidating the Role of Gs-GPCR Signaling at the Bone-Vascular Interface

Award Number: R56DE035489
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2026
PERIOD OF PERFORMANCE END DATE: 08/14/2027

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Elucidating the Role of Gs-GPCR Signaling at the Bone-Vascular Interface - PROJECT SUMMARY Skeletal diseases contribute significantly to morbidity, yet limited therapies exist for building new bone. Understanding the molecular mechanisms driving bone formation is critical for improving skeletal health across the lifespan. Gs-GPCR signaling is a major driver of bone formation, and activating this pathway using recombinant parathyroid hormone (PTH) is an effective treatment strategy for osteoporosis, fractures, and skeletal dysplasias. The anabolic effect of Gs-GPCR activation in osteogenic lineages is well-established, but its role in non-osteogenic cells in the bone niche is poorly understood. There is compelling evidence that cells comprising the bone vasculature play an integral role in skeletal development, maintenance, and repair, yet the role of Gs-GPCR signaling in these lineages and the effect on osteogenesis has not been studied. Fibrous dysplasia of the bone (FD) is a prototypical disease of constitutive Gs-GPCR signaling that leads to expansile, fibrotic bone lesions and massive trabecular bone growth. We and others have used FD as a disease model to delineate the mechanisms by which Gs-GPCR activation in osteogenic lineages drives bone formation. The long- standing paradigm has been that Gs-GPCR signaling in osteoprogenitors drives fibrosis and aberrant osteogenesis in FD. Single-cell RNA sequencing data from human FD bone lesions shows that in addition to osteogenic lineages, endothelial and perivascular cells also harbor GNASR201H/C mutations and express an altered, fibrotic transcriptome. This unexpected finding suggests that Gs-GPCR signaling in vascular cell lineages may contribute to the dramatic FD phenotype and may regulate bone formation more broadly. The overall objective of this proposal is to elucidate the molecular mechanisms by which Gs-GPCR signaling in endothelial and perivascular cells contribute to osteogenesis and fibrosis, using FD as a disease model. Our central hypothesis is that Gs-GPCR signaling in endothelial and perivascular lineages activates critical signaling pathways downstream of Gsa, including VEGF, Wnt/ b-catenin and TGF b/BMP that promote fibrosis and osteogenesis. To test this hypothesis, we implement human induced pluripotent stem cell (hiPSC) models, primary human cells and tissue, and murine models to elucidate the role of Gs-GPCR signaling at the bone- vascular interface. Detailed knowledge of the signaling pathways activated at the bone-vascular interface will help elucidate the mechanisms by which Gs-GPCR signaling in non-skeletal lineages contribute to bone formation. This knowledge can then be leveraged to develop new therapeutics for diseases of impaired osteogenesis, including osteoporosis, fracture repair, and skeletal dysplasias.


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 = $499,022 )
2026	2026	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION, INC.	4150 CLEMENT ST # 151	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	1	8/13/2026	NEW	$499,022
														Subtotal = $499,022

Grand Total All Awards = $499,022

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Elucidating the Role of Gs-GPCR Signaling at the Bone-Vascular Interface

Award Number: R56DE035489

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2026

PERIOD OF PERFORMANCE END DATE: 08/14/2027

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