Novel Pathway and Prevention Strategy for Heterotopic Ossification

DESCRIPTION (provided by applicant): Candidate: I will begin as an Assistant Professor at the University of Michigan with a focus on burn and reconstructive surgery. I recently completed a two-year basic science post-doctoral fellowship studying basic and translational approaches in stem cell and bone biology. My long-term career goal is to achieve scientific independence, and to establish a translational research laboratory to improve diagnostic and treatment strategies for patients with burns, traumatic injuries and heterotopic ossification (HO). Environment: I work within the state-of-the-art Medical Science and Basic Science Research Buildings. My primary mentor, Dr. Wang is a researcher in burn and trauma injury, inflammation pathways and novel imaging modalities. With Dr. Wang, my advisory committee includes well-established experts in bone biology, inflammatory pathways, stem cells, mutant animal development and in vivo imaging. Research: Heterotopic ossification is a common condition seen after burn and trauma injuries. Recent evidence from in vitro and in vivo models in our laboratory suggests that burn injury enhances the osteogenic capacity of mesenchymal stem cells (MSCs) and stimulates HO formation. New mechanistic insight has revealed that burn injury may exert this effect through adenosine triphosphate (ATP) and smad-dependent Bone Morphogenetic Protein Receptor 1A (Bmpr1a) signaling. This osteogenic capacity of MSCs and HO formation is blunted when the burns are treated with an ATP hydrolyzing agent (apyrase). These findings suggest burn injury as a causative factor in HO formation and apyrase as a prevention strategy of HO. --Aim 1. Determine the mechanism of the pro-osteogenic effects of burn injury on MSC osteogenesis and heterotopic ossification. In Aim 1A, we will examine the effect of burn injury on the osteogenic capacity of mouse MSCs from the adipose and bone marrow compartments. Small molecule BMP inhibitors, in addition to the use of MSCs from Bmpr1a mutant mice will be used. In Aim 1B we will explore the role of burn injury on in vivo HO formation using our Achilles tenotomy model. We also will apply this model after global Bmp inhibition and to our Bmpr1a mutant mice to further understand the role of Bmpr1a on HO. --Aim 2: Demonstrate the anti-osteogenic effect of ATP hydrolysis on MSCs and in vivo HO formation. In Aim 2A we will optimize the delivery of the ATP hydrolyzing enzyme apyrase in our mouse burn model and MSCs will be analyzed for their osteogenic capacity. In Aim 2B, we will determine if apyrase application to the burn site can block HO formation using our Achilles tenotomy model. These results will be critical to clinical translation of local ATP hydrolysis as a prevention strategy fr HO. --Summary: This K08 proposal is designed to allow for expedient progress toward my goal of becoming an independent surgeon scientist with a focus on burn injury and heterotopic ossification. This proposal is a logical progression from my previous research experience in MSC osteogenesis and bone development.