Preventing Beta-Cell Apoptosis

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. 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. We have developed four high-throughput cell-based assays (one primary and three secondary) to measure the effects of cytokines on beta cells. Such small molecules could be of potential clinical benefit to early-stage type 1 diabetic patients.

Related Project Pages

  • Genes-to-drugs
  • Target and Pathway ID
  • Small-molecule profiling
  • Transcriptional regulators

Participating Groups

  • Wagner group

Additional Resources