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- W3174112825 abstract "Autoimmune diabetes is characterized by chronic inflammation of pancreatic islets which ultimately destroys insulin-producing β-cells. In the islet, elevated proinflammatory cytokines lead to increased transcription of inducible nitric oxide synthase (iNOS) and its downstream product, nitric oxide (NO). Elevated levels of NO for prolonged periods lead to β-cell apoptosis. The exact causes of autoimmune diabetes are not well defined and, although genetic predisposition is a factor, low concordance rates of autoimmune diabetes among monozygotic twins indicates a role for epigenetic factors. Recent studies suggest that the bromodomain and extraterminal domain (BET) family of epigenetic regulatory proteins contribute to the onset and progression of autoimmune diabetes. BET proteins are epigenetic readers of sites of lysine acetylation found commonly on histones and have emerged as promising drug targets for a wide variety of diseases. We hypothesize that BET proteins increase proinflammatory cytokine-induced transcription in β-cells leading to β-cell damage and that selective inhibition of BET bromodomains with small molecules will prevent or reverse the progression of autoimmune diabetes. Here, we show that BET bromodomain inhibitors decrease the β-cell response to proinflammatory cytokines in an insulinoma β-cell line (INS832/13) and primary rat islets. BET inhibitors attenuated cytokine-induced transcription of inflammatory mediators, including iNOS. This decreased transcription is mediated through inhibition of the NF-κB signaling pathway by BET inhibitors. Using knockdown of individual BET proteins in a β-cell line, we identified the importance of individual BET family members in the altered transcriptional profile characteristic of autoimmune diabetes. This work uncovers important mechanisms of disease onset and progression of autoimmune diabetes, laying the groundwork for more targeted treatments with drug-like small molecules. Disclosure J. Nord: None. S. Wynia-smith: None. B. C. Smith: None. R. Jones lipinski: None. Funding American Diabetes Association (1-18-IBS-068 to B.C.S.); National Institutes of Health (R01DK119359, T32HL134643)" @default.
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- W3174112825 date "2021-06-01" @default.
- W3174112825 modified "2023-09-25" @default.
- W3174112825 title "1258-P: Il-1ß-Induced Transcription of Nf-kB Target Genes Is Repressed by Bet Bromodomain Inhibitors in Pancreatic ß-Cells" @default.
- W3174112825 doi "https://doi.org/10.2337/db21-1258-p" @default.
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