Small-molecule approaches to restore glycemic control in type 1 diabetes Beta-cell death, and the concomitant deficiency in insulin secretion, is a key feature of type 1 diabetes. Loss of glycemic control in type 1 diabetes represents the most direct target for clinical intervention. For decades, the standard of care for type 1 diabetes has been insulin injection. Current approaches to develop new treatments have prioritized islet transplantation and directed stem-cell differentiation, while many technological advances have focused on glucose detection and insulin delivery methods. However, a chemical intervention capable of restoring glycemic control would have enormous impact clinically, by enabling an in vivo pancreatic effect while avoiding the need for immunosuppression. In this Type 1 Diabetes Pathfinder proposal, I describe a chemical biology approach to 1) develop a suite of cell-based assays for high-throughput screening to identify small molecules that prevent cytokine-induced beta-cell death, and 2) use a novel high-throughput metabolic-profiling technology to assess nutrient dependence on pancreatic cell viability and function. Compounds identified in the first approach would serve as candidates for improvement of beta-cell function in cell culture and, ultimately, for therapeutic follow-up. The second approach will enable a metabolic network- dependent dissection of the differences between various pancreatic endocrine and exocrine cell types, and how nutrient metabolism affects beta-cell viability and function. The success of this project has the potential for enormous clinical impact on type 1 diabetes, by paving the way toward the development of novel drugs to prevent beta-cell death and thus restore glycemic control in patients; this project also represents one of the first large-scale efforts to screen for compounds with an impact on beta-cell biology.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
NIH Director’s New Innovator Awards (DP2)
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Special Emphasis Panel (ZDK1-GRB-B (O1))
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Blondel, Olivier
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Broad Institute, Inc.
United States
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Lundh, Morten; Bugliani, Marco; Dahlby, Tina et al. (2017) The immunoproteasome is induced by cytokines and regulates apoptosis in human islets. J Endocrinol 233:369-379
Chou, Danny Hung-Chieh; Vetere, Amedeo; Choudhary, Amit et al. (2015) Kinase-Independent Small-Molecule Inhibition of JAK-STAT Signaling. J Am Chem Soc 137:7929-34
Scully, Stephen S; Zheng, Shao-Liang; Wagner, Bridget K et al. (2015) Synthesis of oxazocenones via gold(I)-catalyzed 8-endo-dig hydroalkoxylation of alkynamides. Org Lett 17:418-21
Dan?ík, Vlado; Carrel, Hyman; Bodycombe, Nicole E et al. (2014) Connecting Small Molecules with Similar Assay Performance Profiles Leads to New Biological Hypotheses. J Biomol Screen 19:771-81
Lundh, M; Scully, S S; Mandrup-Poulsen, T et al. (2013) Small-molecule inhibition of inflammatory ?-cell death. Diabetes Obes Metab 15 Suppl 3:176-84
Yuan, Y; Tang, A J; Castoreno, A B et al. (2013) Gossypol and an HMT G9a inhibitor act in synergy to induce cell death in pancreatic cancer cells. Cell Death Dis 4:e690
Yuan, Yuan; Hartland, Kate; Boskovic, Zarko et al. (2013) A small-molecule inducer of PDX1 expression identified by high-throughput screening. Chem Biol 20:1513-22
Scully, Stephen S; Tang, Alicia J; Lundh, Morten et al. (2013) Small-molecule inhibitors of cytokine-mediated STAT1 signal transduction in ?-cells with improved aqueous solubility. J Med Chem 56:4125-9
Walpita, Deepika; Hasaka, Thomas; Spoonamore, James et al. (2012) A human islet cell culture system for high-throughput screening. J Biomol Screen 17:509-18
Fomina-Yadlin, Dina; Kubicek, Stefan; Vetere, Amedeo et al. (2012) GW8510 increases insulin expression in pancreatic alpha cells through activation of p53 transcriptional activity. PLoS One 7:e28808

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