Core B - Islet Targeting The purpose of this core will be to provide novel technologies for targeting of molecular cargo to pancreatic islets, both in vitro and in living animals, to all three projects in this program. The two novel technologies resident in this core were developed under the auspices of the former Project 3 of this program in the previous five-year funding cycle. The first approach involves application of ultrasound microbubble destruction (UTMD) technology for highly efficient and specific gene delivery to pancreatic islet p-cells of adult animals in vivo. The secondapproach evolved from studies in which we screened an M13 phage display library to identify peptides that bind specifically to pancreatic islet p-cells, and subsequently demonstrated that the cognate phage targets islet p-cells of adult animals in a selective fashion. We believe that these technologies will have different immediate applications to the three projects, so we propose to deploy these technologies in three activity centers: 1) At Duke, Dr. Hans Hohmeier and colleagues will work with Dr. Paul Grayburn to optimize the UTMD technology for delivery of genes to p-cells of living Zucker Diabetic fatty rats, and will then perform studies aimed at reversing or preventing p-cell failure of diabetes in these animals in close collaboration with Project 1;2) At the Baylor Medical Center in Dallas, Dr. Grayburn and colleagues will collaborate closely with Project 3 to develop UTMD-based methods for delivery of targeted transcriptional activators to islet p-cells, in both the in vitro and in vivo settings;3) At UT Southwestern Medical Center in Dallas, Dr. Kathlynn Brown will optimize p-cell targeting peptides for delivery of novel imaging agents to islets in both the in vitro and in vivo settings, in close collaboration with Project 2. We believe that the novel p-cell targeting methodologies resident in Core B provide the PPG team with a remarkable opportunity for rapid translation of discoveries relating to p-cell therapeutic genes (Project 1), novel imaging agents (Project 2), and targeted transcriptional activators (Project 3) to animal models of diabetes, and if proven and validated, to human diabetes therapy.
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