MODIFICATION OF PORCINE ISLETS FOR TRANSPLANTATION

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The goal of this project is to improve the performance and survival of insulin producing cells so they can be transplanted into people with diabetes. The focus is upon porcine islets which will be genetically modified to resist xenograft rejection. The aims are: 1. To use porcine neonatal pancreatic cell clusters (NPCCs) to learn more about how precursor and protodifferentiated pancreatic cells develop into mature endocrine cells. 2. To manipulate replication and differentiation with various growth and differentiation factors to both optimize the tissue source for the transplantation and enhance gene transfer maneuvers. 3. To examine populations of porcine neonatal cells transplanted into nude mice to understand their growth capacity, differentiation and function in vivo 4. To study the characteristics of adenovirus vector-mediated gene transfer and expression in transplanted islets and to establish and characterize a lentivirus-based gene transfer system for islets. Experiments performed with rat islets represent a prelude to experiments with adult and neonatal porcine islets. 5. To determine the extent to which rat islets engineered to express either CTLA4Ig or FasL show enhanced graft survival in a xenogeneic mouse diabetes model and to characterize the requirements for transgene expression and the immune mechanisms involved in graft survival. 6. To establish conditions for the efficient transduction of neonatal porcine islet cells so they can be studied in xenogeneic models.