High throughput methods to identify beta cell modulators
Beta-cell death, and the consequent deficiency in insulin secretion, is a key feature of type 1 diabetes. For decades, the standard of care for this disease has been insulin therapy by intramuscular 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. While cell-based treatments show promise, a chemical intervention capable of restoring glycemic control in type 1 diabetes would have enormous impact clinically, by enabling an in vivo pancreatic effect while avoiding the need for immunosuppression. Bridget’s group is developing phenotypic-cell based assays to find compounds that increase human beta-cell proliferation, that can protect beta cells from the inflammatory processes of diabetes progression, or that can induce beta-cell transdifferentiation, in which other cells in the pancreas take over the role of beta cells by producing insulin themselves.
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2. Chou DH-C, Holson EB, Wagner FF, Tang AJ, Maglathlin RL, Lewis TA, Schreiber SL, and Wagner BK. Inhibition of histone deacetylase 3 protects beta cells from cytokine-induced apoptosis. Chem Biol 2012; 19:669-673. PMCID: PMC3383610
3. Kubicek S, Gilbert JC, Fomina-Yadlin D, Gitlin AD, Yuan Y, Wagner FF, Holson EB, Luo T, Lewis TA, Taylor B, Gupta S, Shamji AF, Wagner BK, Clemons PA, and Schreiber SL. Chromatin-targeting small molecules cause class-specific transcriptional changes in pancreatic endocrine cells. Proc Natl Acad Sci USA 2012; 109:5364-5369. PMCID: PMC3325696
4. Fomina-Yadlin D, Kubicek S, Vetere A, Hu He K, Schreiber SL, and Wagner BK. GW8510 increases insulin expression in pancreatic alpha cells through activation of p53 transcriptional activity. PLoS ONE 2012; 7:e28808. PMCID: PMC3252286
5. Walpita D, Hasaka T, Spoonamore J, Vetere A, Takane KK, Fomina-Yadlin D, Fiaschi-Taesch N, Shamji A, Clemons PA, Stewart AF, Schreiber SL, and Wagner BK. A human islet cell-culture system for high-throughput screening. J Biomol Screen 2012; 17:509-518. Featured image on issue cover.
6. Chou DH-C, Duvall JR, Gerard B, Liu H, Pandya BA, Suh BC, Forbeck EM, Faloon P, Wagner BK, and Marcaurelle LA. Synthesis of a novel suppressor of ?-cell apoptosis via diversity-oriented synthesis. ACS Med Chem Lett 2011; 2:698-702. PMCID: PMC2924935
7. Fomina-Yadlin D, Kubicek S, Walpita D, Dan?ík V, Hecksher-Sørensen J, Bittker JA, Sharifnia T, Shamji A, Clemons PA, Wagner BK, and Schreiber SL. Small-molecule inducers of insulin expression in pancreatic alpha cells. Proc Natl Acad Sci USA 2010; 107:15099-15104. PMCID: PMC2930573
8. Chou DH-C, Bodycombe NE, Carrinski HA, Lewis TA, Clemons PA, Schreiber SL, and Wagner BK. Small-molecule suppressors of cytokine-induced beta-cell apoptosis. ACS Chem Biol 2010; 5:729-734. PMCID: PMC2924935
9. Wagner BK*, Kitami T*, Gilbert TJ, Peck D, Ramanathan A, Schreiber SL, Golub TR, and Mootha VK. Large-scale chemical dissection of mitochondrial function. Nat Biotechnol 2008; 26:343-351 * Equal contributors. (News and Views report in same issue, 26:294-296). PMCID: PMC2715872
Last Updated on September 29, 2020