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Discovery of a Drug Candidate for GLIS3-Associated Diabetes

ABSTRACT: Through development and use of a minimal component protocol for derivation of late stage pancreatic progenitors and beta-like cells, we compared WT and GLIS3-/- pancreatic cells at different stages and discovered that GLIS3-/- cells show an ectopic activation of TGF-beta signaling.

ORGANISM(S): Homo sapiens

PROVIDER: GSE114051 | GEO | 2018/05/05

REPOSITORIES: GEO

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Discovery of a Drug Candidate for GLIS3-Associated Diabetes

Project description:Discovery of a Drug Candidate for GLIS3-Associated Diabetes

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Glis3 regulates pancreatic beta cells development and maturation

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Discovery of a drug candidate for GLIS3-associated diabetes.

Project description:GLIS3 mutations are associated with type 1, type 2, and neonatal diabetes, reflecting a key function for this gene in pancreatic β-cell biology. Previous attempts to recapitulate disease-relevant phenotypes in GLIS3-/- β-like cells have been unsuccessful. Here, we develop a "minimal component" protocol to generate late-stage pancreatic progenitors (PP2) that differentiate to mono-hormonal glucose-responding β-like (PP2-β) cells. Using this differentiation platform, we discover that GLIS3-/- hESCs show impaired differentiation, with significant death of PP2 and PP2-β cells, without impacting the total endocrine pool. Furthermore, we perform a high-content chemical screen and identify a drug candidate that rescues mutant GLIS3-associated β-cell death both in vitro and in vivo. Finally, we discovered that loss of GLIS3 causes β-cell death, by activating the TGFβ pathway. This study establishes an optimized directed differentiation protocol for modeling human β-cell disease and identifies a drug candidate for treating a broad range of GLIS3-associated diabetic patients.

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Glis3 regulates pancreatic beta cells development and maturation

Project description:Glis3 is expressed in pancreatic beta and PP cells. To identify down stream target genes of Glis3, we performed microarray analysis using pancreas total RNAs from 1 week-old WT and Glis3KO2 mice. insulin and pancreatic polypeptide (Ppy) was significantly decreased together with several other Î² cell markers, Glut2 and MafA by microarray analysis. Immunohistochemistry, QRT-PCR, and transmission electron microscopy indicated that postnatal Glis3KO2 pancreas still contains a large population of Î² cells that express Pdx-1, Nkx6.1, and Isl-1; however, insulin production and secretory granules were greatly reduced in these cells. In addition, chromogranin A (ChgA) and Urocortin 3, which are associated with mature Î² cells, was dramatically decreased in Glis3KO2 pancreas. These observations suggest that Glis3 plays a critical role in the maturation of pancreatic Î² cell phenotype. Pancreatic total RNAs were purified from 4 WT and 4 Glis3KO2 at 1 week old age. Then the samples were applied to Agilent mouse genome chip.

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T.F. Glis3: a novel critical player in the regulation of pancreatic beta-cell development and insulin gene expression

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A Glis3-CD133-Wnt signaling axis regulating the self-renewal of adult murine pancreatic progenitor-like cells in colonies/organoids

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Identification of SRSF6 splicing regulatory map and its impact on diabetes susceptibility genes regulation

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