# Dissecting the Cellular and Molecular Mechanisms Contributing to Craniofacial Fibrous Dysplasia

> **NIH NIH K08** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $172,098

## Abstract

PROJECT SUMMARY/ABSTRACT
Craniofacial FD is one of the most common and debilitating skeletal dysplasias. The expansile, fibrous bony
lesions that form in the facial bones and skull base cause significant disability, including dysmorphic facies,
bone fragility, pain, and vision and hearing loss. There are no effective medical treatments for FD, making
this an area of critical medical need. FD can develop in one bone (monoostotic) or multiple bones (polyostotic)
and can occur in association with McCune-Albright Syndrome (MAS), which is a somatic mosaic genetic disease
characterized by FD, precocious puberty, café-au-lait skin lesions, various endocrinopathies, and solid organ
malignancies. FD is arguably the most clinically significant feature of MAS. FD can form at any site within the
skeleton, but the most commonly involved sites are the neural crest-derived craniofacial bones. Despite this,
little is known about the cellular and molecular mechanisms that drive craniofacial FD, and why there is a
predilection for FD formation in neural crest-derived bone. In addition to craniofacial FD, patients with MAS also
commonly have mosaic involvement of other neural crest-derived tissues, including melanocytic skin lesions and
pituitary and adrenal tumors. The goal of this proposal is to better understand the cellular and molecular
mechanisms that drive craniofacial FD so that we can work towards identifying potential treatment targets. We
will pursue this goal through the following 3 aims: Aim 1: Test if WNT inhibition reverses craniofacial FD in
Col1(2.3)+/Rs1+ mice. We have previously modeled FD in mice by activating Gs-GPCR signaling in osteoblastic
cells via the engineered GPCR “Rs1.” Col1(2.3)+/Rs1+ mice develop a dramatic bone phenotype that resembles
human FD. We have shown that stopping the abnormal Gs-GPCR signaling reverses the FD lesions, suggesting
that FD can be reversed. We also found increased levels of WNT expression in bones harvested from these
mice, suggesting that WNT signaling is important in FD. We will use this model to test if inhibition of WNT
signaling can reverse craniofacial FD lesions. Aim 2: Determine the GNASR201H mutational burden in human
craniofacial FD bone and identify the cell type(s) that harbor this mutation. Despite knowing the causative
mutation in FD/MAS, we still do not know which cell type(s) carry the mutation in human FD bone and what level
of mosaicism is needed in order to cause disease. We will use an innovative approach to isolate and genotype
single cells from human craniofacial FD lesions. This will allow us to understand the mutational burden of human
FD lesions and identify the cell type(s) that carry the mutation. Aim 3: Elucidate how the mosaic GNASR201H
mutation affects cell multipotency and differentiation capacity using a human iPSC model of FD/MAS.
We will use our newly-developed human iPSC model of MAS that contains the causative GNAS mutation in its
endogenous locus to explore the effects of G...

## Key facts

- **NIH application ID:** 9996705
- **Project number:** 5K08DE028946-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Kelly Lee Wentworth
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $172,098
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9996705

## Citation

> US National Institutes of Health, RePORTER application 9996705, Dissecting the Cellular and Molecular Mechanisms Contributing to Craniofacial Fibrous Dysplasia (5K08DE028946-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9996705. Licensed CC0.

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