Discovery of a Drug Candidate for GLIS3-Associated Diabetes
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA463329 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description: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.
2018-05-05 | GSE114051 | GEO
Project description:A robust system using disease relevant cells to systematically evaluate the role in diabetes for loci identified through genome wide association studies (GWAS) is urgently needed. Toward this goal, we created isogenic mutant human embryonic stem cell (hESC) lines in GWAS-identified candidate diabetes genes including CDKAL1, KCNQ1 and KCNJ11, and used directed differentiation to evaluate the function of derivative human beta-like cells. The mutations did not affect the generation of insulin+ cells, but impaired insulin secretion both in vitro and in vivo, coinciding with defective glucose homeostasis. CDKAL1-/- insulin+ cells also displayed hypersensitivity to lipotoxicity. A high-content chemical screen identified a candidate drug that rescued CDKAL1-/--specific defects by inhibiting the AP1 (FOS/JUN) pathway. These studies establish a platform using isogenic hESCs to evaluate the function of GWAS-identified loci, and identify a drug candidate that rescues gene-specific defects, paving the way to precision therapy of metabolic diseases.A robust system using disease relevant cells to systematically evaluate the role in diabetes for loci identified through genome wide association studies (GWAS) is urgently needed. Toward this goal, we created isogenic mutant human embryonic stem cell (hESC) lines in GWAS-identified candidate diabetes genes including CDKAL1, KCNQ1 and KCNJ11, and used directed differentiation to evaluate the function of derivative human beta-like cells. The mutations did not affect the generation of insulin+ cells, but impaired insulin secretion both in vitro and in vivo, coinciding with defective glucose homeostasis. CDKAL1-/- insulin+ cells also displayed hypersensitivity to lipotoxicity. A high-content chemical screen identified a candidate drug that rescued CDKAL1-/--specific defects by inhibiting the AP1 (FOS/JUN) pathway. These studies establish a platform using isogenic hESCs to evaluate the function of GWAS-identified loci, and identify a drug candidate that rescues gene-specific defects, paving the way to precision therapy of metabolic diseases.
2016-07-12 | GSE76308 | GEO
Project description:GLIS3 mutations are associated with type 1, type 2, and neonatal diabetes, reflecting a key function for this gene in pancreatic ?-cell biology. Previous attempts to recapitulate disease-relevant phenotypes in GLIS3-/- ?-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 ?-like (PP2-?) cells. Using this differentiation platform, we discover that GLIS3-/- hESCs show impaired differentiation, with significant death of PP2 and PP2-? 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 ?-cell death both in vitro and in vivo. Finally, we discovered that loss of GLIS3 causes ?-cell death, by activating the TGF? pathway. This study establishes an optimized directed differentiation protocol for modeling human ?-cell disease and identifies a drug candidate for treating a broad range of GLIS3-associated diabetic patients.
| S-EPMC6041295 | biostudies-literature
Project description:Today, novel candidate therapeutics are identified in an environment which is intrinsically different from the clinical context in which they are ultimately evaluated. We present a strategy that allows biological relevance to be assessed in the early stages of drug discovery. Using molecular phenotyping and an in vitro model of diabetic cardiomyopathy, we show that by quantifying pathway reporter gene expression, molecular phenotyping can cluster compounds based on pathway profiles and dissect associations between pathway activities and disease phenotypes simultaneously. Molecular phenotyping identified a class of calcium-signaling modulators that can reverse disease-regulated pathways and phenotypes, which was validated by structurally distinct compounds of relevant classes. The technique was applicable to compounds with a range of binding specificities and detected false-positive hits missed by classical phenotypic assays. Our results advocate application of molecular phenotyping in drug discovery, promoting biological relevance as a key selection criterion early in the drug development cascade.
2017-05-24 | GSE89972 | GEO
Project description:Lentiviral-driven discovery of cancer drug resistance mutations
| PRJNA750135 | ENA
Project description:With the advent of automatic cell imaging and machine learning, high-content phenotypic screening has become the approach of choice for drug discovery due to its ability to extract drug-specific multi-layered data, which could be compared to known profiles. In the field of epigenetics, such screening methods have suffered from a lack of tools sensitive to selective epigenetic perturbations. Here we describe a novel approach, Microscopic Imaging of Epigenetic Landscapes (MIEL), which captures the nuclear staining patterns of epigenetic marks (e.g., acetylated and methylated histones) and employs machine learning to accurately distinguish between such patterns. We validated the fidelity and robustness of the MIEL platform across multiple cells lines and using dose-response curves, to insure the robustness of this approach for high content high throughput drug discovery. Focusing on alternative, non-cytotoxic, glioblastoma treatments, we demonstrated that the MIEL assay can identify epigenetically active drugs and classify them by molecular function. Furthermore, we show MIEL was able to accurately rank candidate drugs by their ability to produce a set of desired epigenetic alterations consistent with increased sensitivity to chemotherapeutic agents or with induction of glioblastoma differentiation.
2019-12-29 | GSE134045 | GEO
Project description:Type 1 and type 2 diabetes (T1D and T2D) share pathophysiological characteristics, yet mechanistic links have remained elusive. T1D results from autoimmune destruction of pancreatic beta cells, while beta cell failure in T2D is delayed and progressive. Here we find a new genetic component of diabetes susceptibility in T1D non-obese diabetic (NOD) mice, identifying immune-independent beta cell fragility. Genetic variation in Xrcc4 and Glis3 alter the response of NOD beta cells to unfolded protein stress, enhancing the apoptotic and senescent fates. The same transcriptional relationships were observed in human islets, demonstrating the role for beta cell fragility in genetic predisposition to diabetes.
2016-02-24 | PXD000859 | Pride
Project description:Development of a Large-Scale Chemogenomics Database to Improve Drug Candidate Selection and to Understand Mechanisms of Chemical Toxicity and Action These data support the publication titled "Development of a Large-Scale Chemogenomics Database to Improve Drug Candidate Selection and to Understand Mechanisms of Chemical Toxicity and Action" Copyright (c) 2005 by Iconix Pharmaceuticals, Inc. Guidelines for commercial use: http://www.iconixbiosciences.com/guidelineCommUse.pdf Keywords: other
2005-05-31 | E-GEOD-2409 | biostudies-arrayexpress
Project description:Development of a Large-Scale Chemogenomics Database to Improve Drug Candidate Selection and to Understand Mechanisms of Chemical Toxicity and Action These data support the publication titled "Development of a Large-Scale Chemogenomics Database to Improve Drug Candidate Selection and to Understand Mechanisms of Chemical Toxicity and Action" Copyright (c) 2005 by Iconix Pharmaceuticals, Inc. Guidelines for commercial use: http://www.iconixbiosciences.com/guidelineCommUse.pdf Keywords: other
2005-06-01 | GSE2409 | GEO
Project description:The downregulation of diabetes susceptibility gene GLIS3 contributes to pancreatic beta cell demise, at least in part, through downregulation of the splicing factor SRSF6. Here, we used individual-nucleotide UV crosslinking and immunoprecipitation (iCLIP) to map the RNA binding landscape of SRSF6 in pancreatic beta cells.
2020-12-23 | GSE150172 | GEO