? 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 1 A, 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 1 B 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 2 A 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 2 B, 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 for 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.

Public Health Relevance

More than 60% of major burns, 65% of major combat injuries and 10% of patients who undergo invasive surgery will develop heterotopic ossification which is a debilitating musculoskeletal disease. Current treatment strategies involve surgical extirpation of the heterotopic bone, however, even after a technically successful operation, over 75% of patients suffer from joint contractures and pain. We plan to improve the understanding of the mechanism behind heterotopic ossification and to develop novel diagnostic and prevention strategies using Raman imaging and by targeting inflammation at the injury site with an ATP hydrolyzing agent (Apyrase).

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08GM109105-01
Application #
8618323
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
2014-08-01
Project End
2018-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Surgery
Type
Schools of Medicine
DUNS #
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Agarwal, Shailesh; Loder, Shawn; Cholok, David et al. (2017) Surgical Excision of Heterotopic Ossification Leads to Re-Emergence of Mesenchymal Stem Cell Populations Responsible for Recurrence. Stem Cells Transl Med 6:799-806
Agarwal, Shailesh; Loder, Shawn; Levi, Benjamin (2017) Heterotopic Ossification Following Upper Extremity Injury. Hand Clin 33:363-373
Sorkin, Michael; Cholok, David; Levi, Benjamin (2017) Scar Management of the Burned Hand. Hand Clin 33:305-315
Strong, Amy L; Neumeister, Michael W; Levi, Benjamin (2017) Stem Cells and Tissue Engineering: Regeneration of the Skin and Its Contents. Clin Plast Surg 44:635-650
Friedstat, Jonathan; Brown, David A; Levi, Benjamin (2017) Chemical, Electrical, and Radiation Injuries. Clin Plast Surg 44:657-669
Agarwal, Shailesh; Loder, Shawn J; Cholok, David et al. (2017) Scleraxis-Lineage Cells Contribute to Ectopic Bone Formation in Muscle and Tendon. Stem Cells 35:705-710
Strong, Amy L; Agarwal, Shailesh; Cederna, Paul S et al. (2017) Peripheral Neuropathy and Nerve Compression Syndromes in Burns. Clin Plast Surg 44:793-803
Cholok, David; Lee, Eric; Lisiecki, Jeffrey et al. (2017) Traumatic muscle fibrosis: From pathway to prevention. J Trauma Acute Care Surg 82:174-184
Agarwal, Shailesh; Loder, Shawn J; Breuler, Christopher et al. (2017) Strategic Targeting of Multiple BMP Receptors Prevents Trauma-Induced Heterotopic Ossification. Mol Ther 25:1974-1987
Agarwal, Shailesh; Lloyd, William R; Loder, Shawn J et al. (2017) Combined reflectance and Raman spectroscopy to assess degree of in vivo angiogenesis after tissue injury. J Surg Res 209:174-177

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