The Unfolded Protein Response (UPR) is a coordinated endoplasmic reticulum (ER) stress response program. UPR is initiated whenever protein folding in the ER is reduced and accumulation of malfolded proteins takes place. ER stress is associated with diseases, including type 2 diabetes. However, the dynamics and regulation of the underlying signal transduction network are largely unknown.A first mathematical model for the UPR in mammalian cells was proposed including the PERK and ATF6 pathways. The differential equation model was parameterized from Western blot time course data of phosphorylated PERK and cleaved ATF6 after exposing cells to dithiothreitol (DTT), which prevents the formation of disulfide bonds (DuRose et al. Mol. Biol. Cell, 17: 3095-3107, 2006).Sensitivity analysis showed that only a few kinetic parameters were critical for the predicted p-PERK and ATF6 time responses. Interestingly, variations in these parameters could move the UPR system towards different new steady-states. In certain cases the system returned to its original steady-state while the cells were still exposed to DTT (so-called perfect adaptation). In other cases, the stress sensors remained active. However, the difference in endpoints only emerged after 5 hours, when no experimental data was available. This model-based hypothesis is open for experimental testing.
|Name||FASEB Journal : The Journal of the Federation of American Societies for Experimental Biology|
|Conference||conference; Experimental biology San Diego, United States, April 5-9 2008; 2008-04-05; 2008-04-09|
|Period||5/04/08 → 9/04/08|
|Other||Experimental biology San Diego, United States, April 5-9 2008|