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Sex-Dimorphic Gut of Inflammation and Craniofacial Heterotopic Ossification

Award Number: F30DE035377
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/16/2026
PERIOD OF PERFORMANCE END DATE: 09/15/2031

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Sex-Dimorphic Gut of Inflammation and Craniofacial Heterotopic Ossification - PROJECT SUMMARY/ABSTRACT Craniofacial heterotopic ossification (HO) is a debilitating condition in which bone forms in soft tissues after trauma, surgery, or due to genetic mutations, resulting in pain, physical disabilities, and impairing essential functions like eating and speech. Current treatments for HO focus on managing symptoms and pain, highlighting the urgent need to understand its mechanisms to develop new therapies and improve early diagnosis. The genetic syndrome fibrodysplasia ossificans progressiva (FOP) is marked by episodic flare-ups of ectopic bone and provides critical insights into HO mechanisms. FOP is caused by an ACVR1R206H mutation, where systemic inflammation and macrophage interactions with fibro-adipogenic progenitors (FAPs) play key roles in HO formation. Recent research highlights the influence of the gut microbiome and metabolites on systemic inflammation. Our preliminary data show that gut microbiome ablation decreases HO volume and improves survival in FOP mice, particularly in females, suggesting a sexually dimorphic mechanism. Our metabolomics data reveal sexually dimorphic changes in the abundance of metabolites following gut microbiome ablation, further supporting this mechanism. Therefore, I hypothesize that the gut microbiome influences macrophage-driven inflammation in a sexually dimorphic manner through metabolites, contributing to the development of HO in FOP. This proposal will establish the role of sex hormones, the gut microbiome, and inflammation in HO formation in FOP. Aim 1 will test the contribution of sex hormones, the gut microbiome, and inflammation to HO in FOP. This will be achieved by depleting sex hormones in FOP mice, monitoring the resulting changes in their gut microbiome, and subsequently ablating the microbiome to assess its impact on macrophage-mediated inflammation and trauma-induced HO formation. Aim 2 will test the effect of metabolites on macrophage- driven inflammation and FAP osteogenesis. This aim will investigate the underlying mechanisms contributing to the decreased HO volume and increased survival of female FOP mice with an ablated gut microbiome compared to their male counterparts. To test this, FOP macrophages and FAPs differentiated from patient- derived induced pluripotent stem cells will be exposed to candidate metabolites identified from our preliminary data. Together, these studies are part of a coordinated research and career development plan to develop the applicant’s career as a dentist-scient and investigate the role of the gut microbiome in regulating immune responses and inflammation in HO formation. This training includes mentorship from two highly qualified sponsors, one of which is a clinician-scientist. Research and training will take place at the University of California, San Francisco, which offers an outstanding research environment and an excellent dental school for training.


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 = $50,610 )
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	001	1	9/14/2026	NEW	$0
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	1	9/14/2026	NEW	$50,610
														Subtotal = $50,610

Grand Total All Awards = $50,610

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Sex-Dimorphic Gut of Inflammation and Craniofacial Heterotopic Ossification

Award Number: F30DE035377

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/16/2026

PERIOD OF PERFORMANCE END DATE: 09/15/2031

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