The overall goal of this proposal is to continue our efforts in developing and validating reagents and methods suitable for imaging human islets in the context of islet transplantation and/or type 1 diabetes (TID). Functional imaging of the endocrine pancreas has been difficult, in part because of the many physiologic roles and cell types that characterize the Islets of Langerhans and the exocrine pancreas. During the past year (10/2002- 2/2004) we have used transcript profiling to obtain a map of the genes expressed by human islet tissue, human exocrine pancreas tissue, and other tissues. Using novel informatics techniques we have identified previously unrecognized candidate markers on islets previously thought to be restricted to neuronal and neuroendocrine tissues. This data has clearly revealed specific molecular/functional overlaps between islet cells and cells of neural and neuroendrocrine lineage, allowing us to now take advantage of a large body of experience and research that has focused on functional imaging of the CNS. On the basis of our efforts in identifying islet specific markers we now propose that targeting beta cell vesicular monoamine transporters, type 2 (VMAT2) with PET radioligands will provide quantitative measurements of beta cell mass and function. We have three specific aims that together are designed to provide the necessary preclinical data to move islet imaging via VMAT2 targeting into clinical trials as expediently as possible.
In specific aim one we outline the necessary steps to establish the radiosynthesis of VMAT2 ligands in our PET chemistry laboratory.
Specific aim two focuses on expanding our understanding of the ultrastructural and cell biology of vesicular monoamine transporters type 2 as expressed in beta cells.
In specific aim three we outline a series of studies in animal models of diabetes and islet transplantation designed to show proof of principle (i.e VMAT2 targeting provides quantitative measurements of beta cell mass useful for the management and study human type 1 diabetes and islet transplantation). We have drawn together an interdisciplinary research team of basic cell biologists, transplant surgeons and experts in nuclear medicine with the common goal of developing of imaging reagents and techniques that distinguish islets from its surroundings and provide quantitative measurements of their mass.
| Freeby, Matthew J; Kringas, Patricia; Goland, Robin S et al. (2016) Cross-sectional and Test-Retest Characterization of PET with [(18)F]FP-(+)-DTBZ for ? Cell Mass Estimates in Diabetes. Mol Imaging Biol 18:292-301 |
| Maffei, Antonella; Segal, Ann Marie; Alvarez-Perez, Juan Carlos et al. (2015) Anti-incretin, Anti-proliferative Action of Dopamine on ?-Cells. Mol Endocrinol 29:542-57 |
| Harris, Paul E; Farwell, Michael D; Ichise, Masanori (2013) PET quantification of pancreatic VMAT 2 binding using (+) and (-) enantiomers of [ยน?F]FP-DTBZ in baboons. Nucl Med Biol 40:60-4 |
| Simpson, Norman; Maffei, Antonella; Freeby, Matthew et al. (2012) Dopamine-mediated autocrine inhibitory circuit regulating human insulin secretion in vitro. Mol Endocrinol 26:1757-72 |
| Freeby, Matthew; Ichise, Masanori; Harris, Paul E (2012) Vesicular monoamine transporter, type 2 (VMAT2) expression as it compares to insulin and pancreatic polypeptide in the head, body and tail of the human pancreas. Islets 4:393-7 |
| Harris, P E; Leibel, R L (2012) Neurofunctional imaging of ?-cell dynamics. Diabetes Obes Metab 14 Suppl 3:91-100 |
| Fox, Alice J S; Bedi, Asheesh; Deng, Xiang-Hua et al. (2011) Diabetes mellitus alters the mechanical properties of the native tendon in an experimental rat model. J Orthop Res 29:880-5 |
| Ichise, Masanori; Harris, Paul E (2011) Beta-cell Imaging: Opportunities and Limitations. J Nucl Med : |
| Kwee, Thomas C; Basu, Sandip; Saboury, Babak et al. (2011) Beta-cell imaging: opportunities and limitations. J Nucl Med 52:493; author reply 493-5 |
| Hardy, Mark A; Witkowski, Piotr; Sondermeijer, Hugo et al. (2010) The long road to pancreatic islet transplantation. World J Surg 34:625-7 |
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