Early mitigation of neural inflammation for prevention of trauma-induced heterotopic ossification - Project Summary: Trauma-induced Heterotopic Ossification (tHO) is an extremely painful condition, caused by aberrant bone formation in severely injured soft tissues, with no effectual prophylaxis or treatment. The recent observation that tHO initiation is linked to nociception induced neuroinflammation (NINI), offers a potential therapeutic target. This proposal presents a four-year research career development plan focused on modulating NINI to mitigate tHO formation. The candidate is a board-certified Plastic Surgeon with fellowship training in upper extremity and peripheral nerve surgery, who decided to pivot to a research-oriented academic tract, to study this devastating pathology, given the high prevalence of tHO in high-impact injuries in the candidate’s practice at a Level I trauma center. This proposal builds on his clinical expertise, prior research on osteogenesis, and merges them with two new domains of expertise represented by his mentors Dr. Sean Adams (Vice Chair of Research, UC Davis) – inflammation; and Dr. Benjamin Levi (Chair of Burn Surgery, UTSW) – tHO. The proposed work, didactics, mentorship, and unencumbered research time, will raise the level of the candidate’s science, establish credibility in the tHO research space, and ensure his successful transition to an impactful researcher. Trauma-induced nociception results in sensory nerve over-expression of neuroinflammatory peptide Calcitonin Gene-Related Peptide (CGRP), which activates the Bone Morphogenic Protein (BMP) pathway, causing osteogenic differentiation of resident progenitor cells. Targeted Muscle Reinnervation (TMR) is a peripheral nerve transfer procedure that connects amputated nerve stumps to motor branches in the residual limb of amputees, and significantly reduces pain and neuroinflammation. It is only indicated in cases with intractable pain or phantom pain. Fremanezumab is a CGRP inhibitor currently used in migraine but has not been considered for tHO. The central hypothesis of this proposal is that reducing NINI surgically (TMR) or medically (Fremanezumab) will diminish sensory nerve CGRP expression and ultimately tHO formation. This will be investigated using an in vivo rodent model to test the efficacy of TMR; and a neuroinflammatory in vitro model to test the efficacy of Fremanezumab. Utilizing existing surgical and medical modalities to inhibit NINI in tHO is innovative not only because of their translational potential, but also because of the novel mechanistic insight they provide into tHO initiation and the role of sensory nerve-stem cell communication in it.
