Small-molecule suppressors of cytokine-induced beta-cell apoptosis
Contributors: Schreiber, Stuart L.; Shair, Matthew D.; Saghatelian, Alan
Published: 2012
Language: eng
Description: Type-1 diabetes is caused by the autoimmune destruction of insulin-producing beta cells in the pancreas. Beta-cell apoptosis involves a complex set of signaling cascades initiated by interleukin-1&#946; (IL-1&#946;), interferon-&#947; (IFN-&#947;), and tumor necrosis factor-&#945; (TNF-&#945;). IL-1&#946; and TNF-&#945; induce NF&#954;B expression, while IFN-&#947; induces STAT1 activation. These cytokines lead to a decrease of beta-cell function. The goal of this thesis is to identify small-molecule suppressors of cytokine-induced beta-cell apoptosis using high-throughput screening approach. Using the rat INS-1E beta-cell line, I developed an assay to measure cellular viability after 48 hours of cytokine treatment. I screened 29,760 compounds for their ability to suppress the negative effects of the cytokines. I identified several compounds to be suppressors of beta-cell apoptosis. These efforts led to the discovery of GSK-3&#946; and HDAC3 as novel targets for suppressing beta-cell apoptosis.
Notes: Keywords: beta cells, cytokines, diversity-oriented synthesis, high-throughput screening, histone deacetylase inhibitors, small-molecule probes.

Thesis Ph.D. Harvard University 2012