Date of Completion

Spring 5-1-2026

Thesis Advisor(s)

David J. Goldhamer

Honors Major

Molecular and Cell Biology

Disciplines

Musculoskeletal Diseases

Abstract

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder that primarily affects connective and muscle tissues. It is characterized by heterotopic ossification (HO), which is the formation of bone tissue where it does not normally form. HO can be triggered by physical trauma, infection, inflammation, or stress. The formation of HO leads to impaired muscle function and reduced patient quality of life. Concurrently, the loss of muscle function indicates there is an impairment in the ability of the muscle to regenerate effectively. The most common genetic cause of FOP is an arginine-to-histidine substitution within the type I bone morphogenic protein receptor (BMPR) Activin A receptor type 1 (ACVR1). This renders ACVR1 responsive to Activin A, causing aberrant pathogenic BMP signaling. We recreated the disease environment by targeting the Acvr1 mutation expression to fibro-adipogenic progenitors (FAPs).

In contrast to previous FOP studies, which primarily induce HO through direct muscle injury, our work investigates the role of the fascia and FAPs in HO initiation without directly damaging the muscle tissue. Using a mouse model in which Acvr1tnR206H  expression was targeted to FAPs we showed that a minor fascial injury is sufficient to induce robust HO and muscle degeneration in regions of muscle adjacent to the injury. Additionally in this injury model muscle does not regenerate properly.  This model allows us to explore the role of Acvr1tnR206H expressing FAPs in muscle degeneration and failed regeneration observed in FOP.

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