Drishti Maniar
BME PhD Proposal Presentation
Date: 2024-11-04
Time: 4:00 PM-5:45 PM
Location / Meeting Link: 3029 Krone Engineered Biosystems Building (EBB) / https://gatech.zoom.us/j/94063656082?pwd=IqXnZlblNFxL9VnuhFebs86ENMo8tK.1
Committee Members:
Krishnendu Roy, Ph.D. (Advisor); Leslie Chan, Ph.D. ; Ankur Singh, Ph.D. ; Younan Xia, Ph.D. ; Robert Guldberg, Ph.D.
Title: Immunoengineered Strategies to Modulate Systemic Immune Dysregulation and Immunosuppression Following Musculoskeletal Trauma
Abstract:
Severe musculoskeletal trauma is a major clinical concern, accounting for up to 78% of non-fatal trauma-related injuries. These injuries often lead to serious complications, with bone nonunion in long-bone fractures being particularly challenging. Post-traumatic bone nonunion results in significant clinical challenges, including extended hospital stays, multiple surgeries, potential limb amputations, and in severe cases, mortality. Traumatic injuries, especially those involving substantial bone and muscle loss or bacterial infection, not only hinder local healing but also lead to systemic immune dysregulation and immunosuppression (SIDIS). A key characteristic of SIDIS is the increase of immune suppressor cells, including myeloid-derived suppressor cells (MDSCs). Despite awareness of SIDIS in trauma survivors, the early immune cellular and molecular mechanisms underlying this systemic immune dysfunction remains poorly understood. This knowledge gap has impeded the development of effective interventional strategies to address SIDIS, restore immune homeostasis, and improve functional bone regeneration. Previous attempts at immunomodulation—targeting cytokines, growth factors, or using stem cells—have shown limited success in restoring immune homeostasis following SIDIS. Current immunotherapies for MDSC depletion, especially in cancer immunotherapy, include free monoclonal antibodies (mAbs) or small molecule drugs. However, these therapeutics pose several limitations, including off-target toxicity, complex manufacturing processes, high costs, and short retention time. To overcome these challenges, we propose a three-aim approach. First, we will utilize single-cell RNA sequencing to analyze both systemic and local immune microenvironments in a pre-clinical rat trauma model. Our focus will be on characterizing MDSCs to identify a distinct subpopulation within them, which we term trauma immunosuppressive myeloid (TIM) cells. We propose that TIM cells play a critical role in driving systemic immunosuppression and disrupting immune homeostasis following trauma (Aim 1). Second, we will develop synthetic nanoparticle antibodies that mimic the specificity and functionality of mAbs and liposomal nanoparticles encapsulating doxorubicin to target and deplete TIM cells (Aim 2). Finally, we will test these immunomodulatory TIM cell targeting therapeutics in established pre-clinical models of trauma-induced SIDIS. These models will include concomitant bone-muscle damage or bone defect with infection (Aim 3). Given the role of TIM cells in perpetuating systemic immunosuppression, our central hypothesis is that depleting TIM cells systemically will restore immune homeostasis and enhance bone regeneration following severe musculoskeletal trauma. This work will identify early immune biomarkers of SIDIS, guide the development of TIM-targeting strategies in-vitro, and potentially improve bone regeneration outcomes in-vivo. Achieving successful restoration of immune homeostasis, combined with targeted local regenerative therapies, could significantly enhance recovery and improve patient outcomes following severe musculoskeletal trauma.
