This project is focused on a systems biology approach to skin rejection in the setting of vascularized composite allotransplantation (VCA). The skin of VCAs, such as hand or face transplants, is a major site for inflammation driven by cytokines and chemokines. Despite insights into acute rejection and progress in grading of skin rejection, the complexity of inflammation is not yet entirely understood. We hypothesize, based on preliminary data from translational studies, that profiling of gene and protein markers in graft tissue components will enable reliable monitoring, prediction, and early diagnosis of acute rejection in VCA. We propose to elucidate protein-level cytokine/chemokine and gene expression patterns in skin and muscle after VCA (Aim 1). We also propose to develop computational models of rejection to facilitate timely prediction and prevention of rejection (Aim 2). The proposed studies offer an unparalleled opportunity for systematic, objective, quantitative, biology-oriented analysis of molecular mechanisms involved in VCA. Our methodology, proven in related fields such as traumatic injury, could pave the way for novel, personalized anti-rejection strategies in VCA, thereby improving overall quality of life for injured Warfighters with devastating and disabling injuries that are not treatable using current strategies. |
