The overall goal of the proposed research is to develop, optimize, and evaluate novel nuclear imaging methods for quantifying pancreatic islet cell mass in vivo. Approaches to noninvasively assay islet cell mass are greatly needed because these would lead to a better understanding of the pathogenesis of diabetes, provide an early diagnostic marker for type 1 and type 2 diabetes, and accelerate the development and evaluation of new therapies. Through considerable efforts by many investigators, a number of radiotracers targeting various islet receptors or processes have been evaluated for islet imaging but have thus far not proven useful for quantifying islet mass in humans. The small size of islets, their low abundance, and their scattered distribution create considerable challenges for non-invasive methods to quantify islet cell mass. This proposal outlines a new interdisciplinary approach using optical and nuclear imaging with antibodies highly specific for the surface of islet cells that were recently developed in the Beta Cell Biology Consortium. In order to overcome the slow radiotracer clearance and high non-target tissue background that has hindered previous antibody-based imaging agents, we will use a pretargeting approach proven useful in tumor targeting and preliminary studies of islet cell imaging. This pretargeting strategy overcomes the prior limitations associated with antibody-based imaging by employing a three-step protocol of sequentially injecting the antibody, then a clearance agent, and lastly the radio labeled effectors. The ability of our pretargeting and clearance approach to image islet mass will be evaluated using unique pre-clinical models that combine bioluminescence imaging of the beta cell, specific beta-cell ablation, and multimodal imaging with co-registration of tomographic images to spatially delineate increased or decreased islet mass.
The ability to measure pancreatic islet cell mass would lead to a better understanding of the pathogenesis of diabetes, provide an early diagnostic indicator of type 1 and type 2 diabetes, and accelerate the development and evaluation of new therapies. The proposed research seeks to develop, optimize, and evaluate novel nuclear imaging methods for quantifying pancreatic islet cell mass in vivo.
|Saunders, Diane; Powers, Alvin C (2016) Replicative capacity of Î²-cells and type 1 diabetes. J Autoimmun 71:59-68|
|Dai, Chunhua; Kayton, Nora S; Shostak, Alena et al. (2016) Stress-impaired transcription factor expression and insulin secretion in transplanted human islets. J Clin Invest 126:1857-70|
|Virostko, John; Hilmes, Melissa; Eitel, Kelsey et al. (2016) Use of the Electronic Medical Record to Assess Pancreas Size in Type 1 Diabetes. PLoS One 11:e0158825|
|Dou, Shuping; Virostko, John; Greiner, Dale L et al. (2015) Quantitative Correlation of in Vivo Properties with in Vitro Assay Results: The in Vitro Binding of a Biotin-DNA Analogue Modifier with Streptavidin Predicts the in Vivo Avidin-Induced Clearability of the Analogue-Modified Antibody. Mol Pharm 12:3097-103|
|Zhu, Xiaodong; Hu, Ruiying; Brissova, Marcela et al. (2015) Microtubules Negatively Regulate Insulin Secretion in Pancreatic Î² Cells. Dev Cell 34:656-68|
|Kayton, Nora S; Poffenberger, Gregory; Henske, Joseph et al. (2015) Human islet preparations distributed for research exhibit a variety of insulin-secretory profiles. Am J Physiol Endocrinol Metab 308:E592-602|
|Dou, Shuping; Virostko, John; Greiner, Dale L et al. (2015) A feasible approach to evaluate the relative reactivity of NHS-ester activated group with primary amine-derivatized DNA analogue and non-derivatized impurity. Nucleosides Nucleotides Nucleic Acids 34:69-78|
|Patel, Manishkumar; Gleason, Alexa; O'Malley, Stacey et al. (2014) Non-invasive bioluminescence imaging of Î²-cell function in obese-hyperglycemic [ob/ob] mice. PLoS One 9:e106693|
|Dou, Shuping; Virostko, John; Rusckowski, Mary et al. (2014) Differentiation between temporary and real non-clearability of biotinylated IgG antibody by avidin in mice. Front Pharmacol 5:172|
|Dou, Shuping; Wang, Yuzhen; Barton, Bruce et al. (2014) Comparison between two labeled agents in mice using a coinjection-ratio approach in contrast to a conventional group approach. Nucl Med Biol 41:127-31|
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