? In vivo imaging of pancreatic islets can provide invaluable information about the life cycle of endogenous and/or transplanted beta-cells in type 1 diabetes. Current in vivo imaging attempts have focused on quantification of islet mass, secretory products, or inflammatory markers. In contrast to microscopy, magnetic resonance imaging (MRI) can non-invasively deliver high resolution images in vivo, and was recently reproducibly utilized to visualize transplanted islets. Although successful early vascularization of islet grafts is pivotal for long-term islet survival and function, limited in vivo information is available on the time course of angiogenesis in transplanted islets. We have previously demonstrated a rise of hypoxia-inducible factor (HIF-1a) prior to microscopic evolution of vascularization in murine islet grafts in the early post-transplant period. Moreover, we showed positive effects of pre-transplant culture of islets in nerve growth factor (NGF), and of hyperbaric oxygen therapy (HBO) of recipients, on islet graft survival and function. Angiogenesis can be detected with magnetic resonance imaging (MRI) via change in contrast enhancement of tissue over time. The main hypothesis of this proposal is that dynamic contrast-enhanced (DCE) -MRI can be used for real time assessment of vascularization in transplanted human islets.
The specific aims are: 1. To utilize MRI in developing a novel vascularization-focused approach for visualization of transplanted humans islets; 2. To test the relationship between angiogenesis measured by MRI and islet graft survival and function; and 3. To reduce hypoxia-associated beta-cell apoptosis in islet transplantation using a novel combined NGF/HBO strategy monitored by DCE-MRI. The short-term goal is to extend DCE-MRI data on normal and accelerated angiogenesis generated by this proposal to a clinical model of islet transplantation in the imminent future. This would provide an invaluable tool for monitoring islets following transplantation, detecting early changes in islet vasculature, and allowing earlier intervention to salvage and prolong islet graft function. The long-term goal is for DCE-MRI, in combination with other in vivo imaging approaches, to provide a comprehensive non-invasive real time picture of native and transplanted beta-cells, which would ultimately enable the development of a successful cure for type 1 diabetes. ? ? ?
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