Chapter 30 Small-Scale Modeling Approach and Circuit Wiring of the Unfolded Protein Response in Mammalian Cells Rodica Curtu and Danilo Diedrichs Abstract The accumulation of unfolded proteins in the endoplasmic reticulum (ER) activates a mechanism whose primary functions are to sense any perturbation in the protein-folding capacity of the cell, and correct the situation to restore home- ostasis. This cellular mechanism is called the unfolded protein response (UPR). We propose a biologically plausible computational model for the UPR under ER stress in mammalian cells. The model accounts for the signaling pathways of PERK, ATF6, and IRE1 and has the advantage of simulating the dynamical (timecourse) changes in the relative concentrations of proteins without any a priori steady-state assumption. Several types of ER stress can be assumed as input, including long- term (eventually periodic) stress. Moreover, the model allows for outcomes ranging from cell survival to cell apoptosis. Keywords Endoplasmic reticulum stress  Unfolding protein response  Signaling pathways  PERK  ATF6  IRE1 30.1 Introduction The endoplasmic reticulum (ER) is a large intracellular organelle that plays an essential role to the functionality and survival of the cell; it is a major calcium storage site as well as a site where secretory and membrane proteins are modified, folded, and assembled. Perturbations to the ER that affect its protein-folding capacity can be induced in several ways, for example, through pathogenic infec- tions, chemical insult, genetic mutation, or nutrient deprivation. Consequently, the ER experiences an accumulation of unfolded or misfolded proteins, a situation which is generally termed ER stress [10]. The cellular mechanism that addresses R. Curtu (*) Department of Mathematics, University of Iowa, Iowa City, IA 52242, USA e-mail: rodica-curtu@uiowa.edu H.R. Arabnia (ed.), Advances in Computational Biology, Advances in Experimental Medicine and Biology 680, DOI 10.1007/978-1-4419-5913-3_30, # Springer ScienceþBusiness Media, LLC 2010 261