The overall goal of our studies is to develop reagents suitable for imaging human islets in the context of islet transplantation or type 1 diabetes. In this islet marker discovery program, we will borrow heavily from tumor immunology using the antigen mining techniques of gene expression analysis, bioinformatics, serology and protein chemistry.
In Specific Aim One, we combine these methods to characterize the cell surface of human islet tissue. We will use two convergent strategies to identify candidate islet specific markers. In part A, transcript profiling will be used to obtain a map of human islet, exocrine pancreas and liver tissue gene expression. This information will allow us to generate Venn diagrams of candidate markers that are expressed by human islets and not by the exocrine component of the pancreas and not by the liver. Alternate nucleic acid based methods will be used to validate the tissue specificity and distribution of candidate markers determined by transcript profiling. In part B, we will use an adaptation of the serological analysis of recombinant cDNA expression libraries (SEREX) technique (a.k.a., antibody screening of phage expression libraries) to identify islet cell surface associated molecules that may be useful in imaging. Expression libraries will be created in a unique manner as to remove genes that are expressed both in islets and in the exocrine component of the pancreas (or liver). Candidate marker proteins will then be expressed in bacterial systems for the generation of specific antisera.
In Specific Aim Two, we will characterize the biodistribution and uptake kinetics of radiolabeled antibodies recognizing candidate markers. We will explore and compare the ability of Dithizone based and immunoglobulin (Ig) based radiolabel imaging reagents to detect islet tissue in vivo. In the last phase of the proposal we shall determine whether these reagents can be used as magnetic resonance imaging (MRI) contrast reagents. In these preclinical studies we will determine whether human islets, transplanted into an immunodeficient animal model, can be detected using reagents modified for use in non-invasive magnetic resonance (MR) imaging studies. We have drawn together an interdisciplinary research team of cell biologists, tumor antigen biologists, transplant surgeons and medical physicists with a common goal of developing of imaging reagents and techniques that distinguish islets from their surrounding tissue.
| 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 [¹?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 |
| 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 |
| 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 : |
| 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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