Glutamine-Targeted Therapies to Prevent Traumatic Heterotopic Ossification
Abstract
FY22 PRORP Focus Area to be addressed: The proposed project directly relates to the FY22 PRORP Focus Area of Retention Strategies, including Return to Duty: Treatment strategies that can be utilized along the continuum of care and enable return to duty within 1 year of injury and Composite Tissue Regeneration including techniques aimed at improving outcomes following high-energy extremity trauma, with a focus on improving wound healing. The proposal is an applied research collaboration between a basic scientist and a clinician scientist whose laboratories were established to improve the outcomes of combat casualties and civilians after musculoskeletal trauma. This proposal specifically seeks to further determine the role of the amino acid glutamine in extremity trauma, with an end-goal of validating a translational approach to prevent aberrant extremity wound repair as seen in heterotopic ossification (HO). With dramatic improvements in survival from combat-related blast injuries due to tourniquet use, we have witnessed a concomitant increase in patients with debilitating injuries that drastically diminish quality of life. Of the nearly 15,000 battle injuries suffered in Operations Iraqi Freedom/New Dawn and Enduring Freedom, over 50% of those injuries were extremity injuries. Of these wounded Soldiers with extremity injuries, over 60% of them will go on to develop HO. HO also causes significant disability in hundreds of thousands of civilians and Veterans with joint arthroplasties, amputations, and orthopedic injuries. For example, over 80% of patients with fractures and revision joint replacements will develop HO. As a result of forming bone outside of the skeleton, HO causes severe chronic pain, open wounds, and limited range of motion. Current treatment strategies address HO after its development with surgical excision. However, surgery is unable to restore range-of-motion, which has often been chronically limited due to HO, cannot address chronic pain, and causes prolonged wounds with poor healing. After excision, patients often develop recurrence within the original tissue bed, which necessitates re-excision, or continues to cause the original signs and symptoms. Though several prophylactic medications have been previously trialed, all have negative side effects, and all fail to target the causative signaling mediators that lead to HO. Identifying a cohesive and timed strategy to prevent acute HO would greatly improve outcomes following high-energy extremity trauma as well as enhance return to duty. We believe glutamine metabolism in the causative initiator and can be targeted early through diet or drugs to prevent traumatic HO. Potential clinical applications, benefits, and risks: This proposal is designed to be translatable and simulates the real-world trauma and management that patients may expect to receive. First, we use clinically relevant models of trauma-induced HO, which are broadly applicable to combat-wounded military personnel and to civilians with significant trauma. Secondly, we utilize dietary modifications and a near clinical pharmacotherapy strategy targeting glutamine transport in the bone formation pathway; this method is highly translatable, cost-effective, and easily implemented. Thirdly, this proposal addresses duration of treatment by selecting a short time period of treatment to minimize cost, improve adherence, and avoid adverse consequences. The combination of these techniques makes this proposal an important preclinical study that lends itself to establishing key data necessary to push forward definitive clinical trials. Projected timeline and expected patient-related outcomes: In this proposal, we plan to rapidly deploy our optimized nutrition protocol and pharmacologic treatment interventions. In the first 12 months we will validate our dietary strategy to prevent HO in our proven extremity trauma models. In months 12-36, we will demonstrate the ability to
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310519
Entities
People
- Courtney Karner
Organizations
- United States Army
- University of Texas Southwestern Medical Center