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
Bridget Wagner,Broad Institute,Cambridge, MA,firstname.lastname@example.org,617-714-7363
Danny Chou,Broad Institute,Cambridge, MA,email@example.com
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.
Diabetes, apoptosis, cytokine, beta cells, insulin
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
Data Table (Concise)