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BioAssay: AID 435007

Summary of Broad Institute MLPCN Beta Cell Apoptosis Inhibition Project

The goal of this project is to identify molecules that prevent apoptosis in pancreatic beta cells that is induced by a combination of cytokines, namely Interferon-gamma, Interleukin 1-beta and tumor necrosis factor-alpha. ..more
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Probe(1)
 
 
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 Related BioAssays
AID: 435007
Data Source: Broad Institute (2061-01_INHIBITORS)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
BioAssay Version:
Deposit Date: 2010-06-21
Modify Date: 2011-09-29

Data Table ( Complete ):           View Active Data    View All Data
BioActive Compound: Chemical Probe: 1    Active: 1
Related Experiments
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AIDNameTypeComment
435005Luminescence Cell-Based Primary HTS to Identify Inhibitors of Beta Cell Apoptosis.Screeningdepositor-specified cross reference: Primary HTS
449756Luminescence Cell-Based Dose Retest to Confirm Inhibitors of Beta Cell ApoptosisConfirmatorydepositor-specified cross reference
463206Luminescence Cell-Based Counter Screen to Identify Inhibitors of Cytokine Induced ApoptosisConfirmatorydepositor-specified cross reference
463229ATP-based Luminescence in the Absence of Cytokines Measured in Cell-Based System Using Plate Reader - 2061-06_Inhibitor_Dose_CherryPickConfirmatorydepositor-specified cross reference
488844Detect Cellular ATP-levels in INS-1E Cells Measured in Cell-Based System Using Plate Reader - 2061-01_Inhibitor_Dose_DryPowder_ActivityConfirmatorydepositor-specified cross reference: Retest at dose for primary HTS hits
488848Apoptosis Measured in Cell-Based System Using Plate Reader - 2061-02_Inhibitor_Dose_DryPowder_ActivityConfirmatorydepositor-specified cross reference: Testing compounds for reduction of caspase activity in INS-1E cells challenged with cytokine and glu
488864ATP-based Luminescence in the Absence of Cytokines Measured in Cell-Based System Using Plate Reader - 2061-06_Inhibitor_Dose_DryPowder_ActivityConfirmatorydepositor-specified cross reference: Testing compounds for effect on viability in INS-1E cells in the absence of cytokine
488866Nitrite Measured in Cell-Based System Using Plate Reader - 2061-04_Inhibitor_Dose_DryPowder_ActivityConfirmatorydepositor-specified cross reference: Testing compounds for effect on nitrite production as a measure of apoptosis
488867Apoptosis Measured in Cell-Based System Using Plate Reader - 2061-03_Inhibitor_Dose_DryPowder_Activity_Set2Confirmatorydepositor-specified cross reference: Testing additional round compounds to assess mitochondrial depolarization in INS-1E cells challenged
488868Nitrite Measured in Cell-Based System Using Plate Reader - 2061-04_Inhibitor_Dose_DryPowder_Activity_Set2Confirmatorydepositor-specified cross reference: Testing additional round compounds for effect on nitrite production as a measure of apoptosis
488870Nitrite Measured in Cell-Based System Using Plate Reader - 2061-04_Inhibitor_Dose_DryPowder_Activity_Set3Confirmatorydepositor-specified cross reference: Testing additional round compounds for effect on nitrite production as a measure of apoptosis
488910Detect Cellular ATP-levels in INS-1E Cells Measured in Cell-Based System Using Plate Reader - 2061-01_Inhibitor_SinglePoint_HTS_ActivityScreeningdepositor-specified cross reference: Primary HTS on additional library compounds
488931Apoptosis Measured in Cell-Based System Using Plate Reader - 2061-03_Inhibitor_Dose_DryPowder_ActivityConfirmatorydepositor-specified cross reference: Testing compounds to assess mitochondrial depolarization in INS-1E cells challenged with cytokine an
488936Apoptosis Measured in Cell-Based System Using Plate Reader - 2061-02_Inhibitor_Dose_DryPowder_Activity_Set2Confirmatorydepositor-specified cross reference: Testing additional round compounds for reduction of caspase activity in INS-1E cells challenged with
488945Primary Beta Cell Apoptosis assay Measured in Cell-Based System Using Plate Reader - 2061-07_Inhibitor_Dose_DryPowder_Activity_Set2Confirmatorydepositor-specified cross reference: Testing compounds for reduction of caspase activity in primary human islet cells challenged with cyt
488951Primary beta islet insulin ELISA Measured in Cell-Based System Using Plate Reader - 2061-09_Inhibitor_Dose_DryPowder_ActivityConfirmatorydepositor-specified cross reference: Testing compounds for effect on glucose-induced insulin secretion in primary human islet cells
488959Glucose-induced Insulin secretion ELISA Measured in Cell-Based System Using Plate Reader - 2061-05_Inhibitor_Dose_DryPowder_ActivityConfirmatorydepositor-specified cross reference: Testing compounds for effect on glucose-induced insulin secretion in INS-1E cells
652090Quantitative proteomics to determine protein binders to ML187Otherdepositor-specified cross reference
652132Effect of ML-187 on cytokines-mediated increase in STAT1 level and activationOtherdepositor-specified cross reference
652171Validation of the affinity reagent probe (ML-187) with a PEG linker: comparison of ML-187-PEG and ML-187 cell-based efficacy Measured in Cell-Based System Using Plate Reader - 2061-11_Inhibitor_Dose_DryPowder_ActivityOtherdepositor-specified cross reference
652206ML-187 activity in a kinase panel for Extended probe characterization for beta-cell apoptosis Measured in Biochemical SystemOtherdepositor-specified cross reference
652234Binding of ML-187 to Usp9x as assessed by surface plasmon resonance Measured in Biochemical SystemOtherdepositor-specified cross reference
652237Effect of siRNA-mediated knock down of binding partners of ML-187 on cytokine-induced apoptosis cell-deathOtherdepositor-specified cross reference
652238Effects of siRNA knock down of Usp9x (a target of ML-187) on cytokine-induced beta-cell death (Cell Titer Glo) Measured in Cell-Based System Using Plate ReaderOtherdepositor-specified cross reference
652240Effects of siRNA knock down of Usp9x (a target of ML-187) on cytokine-induced apoptosis (Caspase activity) Measured in Cell-Based System Using Plate ReaderOtherdepositor-specified cross reference
Description:
Primary Collaborators:
Bridget Wagner,Broad Institute,Cambridge, MA,bwagner@broadinstitute.org,617-714-7363
Danny Chou,Broad Institute,Cambridge, MA,dchou@broadinstitute.org

Project Goal:
The goal of this project is to identify molecules that prevent apoptosis in pancreatic beta cells that is induced by a combination of cytokines, namely Interferon-gamma, Interleukin 1-beta and tumor necrosis factor-alpha.

Keywords:
Diabetes, apoptosis, cytokine, beta cells, insulin

Biological Relevance:
Type 1 diabetes is caused by autoimmune destruction of insulin-producing beta cells in the pancreas. Human beta-cell apoptosis in this process involves a complex set of signaling cascades initiated by interleukin-1b (IL-1b), interferon-g (IFN-g), and tumor necrosis factor-a (TNF-a). IL-1b and TNF-a induce NFkB expression, while downstream activation of gene expression is thought to occur through nitric oxide (NO) signaling, which both increases the endoplasmic reticulum stress-response pathway and decreases beta-cell function. These effects of cytokines are beta cell-specific, and we aim to find small-molecule suppressors that would have little to no effect on other cell types in the pancreas.

Small molecules that increase beta-cell survival in the presence of cytokines could be of potential clinical benefit to early-stage type 1 diabetic patients. A number of studies have described small molecules with protective effects in the presence of cytokines; most of these were discovered because of their antioxidant or anti-inflammatory effects. Further, small-molecule inhibition of histone deacetylases (HDAC) with suberoylanilide hydroxamic acid (SAHA) or trichostatin A (TSA) can prevent cytokine-induced beta-cell death, presumably by decreasing NFkB transactivation. Therefore, multiple mechanisms may serve to protect beta cells from cytokine-induced apoptosis.
Categorized Comment - additional comments and annotations
From MLP Probe Report:
Probe count: 1
MLP Probe ML# for probe 1: ML187
PubChem Substance ID (SID) for probe 1: 99376568
PubChem Compound ID (CID) for probe 1: 46907798
IC50/EC50 (nM) for probe 1: 3500
Target for probe 1: Cytokine induced beta cell apoptosis
Anti-target for probe 1: Beta-cell apoptosis in the absence of cytokines
Fold selectivity for probe 1: >10
NCBI Book chapter link for probe 1: http://www.ncbi.nlm.nih.gov/books/NBK65431/ (ID: 2642214)
Grant number for probe 1: DK083048
NCBI Book chapter title for probe 1: Identification of Small Molecule Inhibitors that Suppress Cytokine-Induced Apoptosis in Human Pancreatic Islet Cells
Result Definitions
TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
Additional Information
Grant Number: DP2 DK083048

Data Table (Concise)
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