Tracheal loss is a devastating condition and the trachea remains one of the remaining vital organs for which there is no adequate substitute. Attempts at engineering tracheal transplants from either synthetic constructs or decellularized tracheal scaffolds have met with limited success including long and complication-filled secondary healing and catastrophic tracheal luminal collapse. This proposal will investigate newly identified signaling pathways and the role that they play in limiting cellular and tissue regeneration, engraftment and tracheal angiogenesis. Knowledge gained from experiments in our unique murine model of orthotopic tracheal transplant will be translated into generating a functional """"""""shovel-ready"""""""" human trachea.
Tracheal loss is a devastating condition, and the trachea is one of the remaining vital organs for which there is no adequate substitute. Current approaches with stents, tracheal lengthening surgery and tracheal transplantation have significant problems and limited application. Attempts at engineering tracheal transplants from either synthetic constructs or decellularized tracheal scaffolds have met with only modest success, including long and complication-filled secondary healing and catastrophic tracheal luminal collapse. However, the underlying reasons for the persistent barrier to tracheal engineering remain largely undefined. This proposal will investigate newly-identified signaling pathways and the role that they play in limiting cellular and tissue regeneration, engraftment and tracheal angiogenesis. We have discovered an as of yet unappreciated signal transduction mechanism that is activated during the process of tracheal engineering and that inhibits cellular take and restoration of blood flow in bioengineered transplanted tracheas. We will be therapeutically interrupting this signal to increase tracheal engraftment and transplantation. Knowledge gained from experiments in our unique murine model of orthotopic tracheal transplant will be translated into generating a functional shovel-ready human trachea.
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