This R21 application aims at exploring the feasibility of a novel approach to address the Program announcement area of interest on the development of cell therapies to treat diabetes. Pancreatic islet transplantation is becoming an alternative to insulin therapy in patients suffering from the most severe forms of Type 1 diabetes. However, a major obstacle to success of islet transplantation is early graft loss mediated by apoptosis and necrosis induced by the instant blood-mediated inflammatory reaction (IBMIR), occurring after transplantation of islets into liver. IBMR is a clotting reaction characterized by rapid platelet deposition on islet surface, activation of the coagulation and complement cascades, and leukocyte infiltration of the islets. A critical molecule causing IBMR is tissue factor (TF), a natural mediator of coagulation. TF is known to be present in isolated islets and its expression is tightly associated with islet graft failure. The basic idea is to engineer a molecule that could efficiently prevent the production of TF in islets. We propose to develop a chimeric molecule composed of two domains: a protein transduction domain (PTD), to warrant molecule distribution throughout the whole islets and a specific anti-gene peptide nucleic acid (PNA) component that will block transcription of TF gene. To develop this project we will synthesize and characterize TAT-PNA molecules at the molecular level and will test their efficiency to inhibit IBMIR using a relevant in vivo model of islet transplantation. The development of such a novel PTD-antiTF PNA reagent, may allow the in vitro treatment of islets preceding transplantation in order to obliterate the IBMR toxic effects and thus increasing the successful outcome of transplantation. Such approach could minimize necessity for multiple transplants thus reducing the problem due to the shortage of cadaveric donor pancreata available for islet transplantation. ? ? ?
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