THE APOE-/- MOUSE PHYSIOLAB® PLATFORM: A DYNAMIC MODEL FOR PREDICTING THE IMPACT OF CIGARETTE SMOKE EXPOSURE ON ATHEROSCLEROTIC PLAQUE PROGRESSION

Abstract

Atherosclerosis is a complex, multi-pathway disease for which cigarette smoke exposure is a known risk factor. The Apoe-/- mouse is a widely used pre-clinical animal model for atherosclerosis research, and is commonly used to assess the impact of disease-modifying genes, risk factors, and treatments on plaque progression. It is therefore of significant interest to understand how results obtained in these mice may translate to the clinical setting. Doing so, however, requires detailed knowledge of (a) the mechanisms underlying the disease etiology, (b) the relative importance of these mechanisms as drivers of progression, and (c) how these roles change in response to perturbation. To address these questions, we have developed a large-scale mathematical model of atherosclerosis in the Apoe-/- mouse. The model simulates plaque growth in the brachiocephalic artery and aortic arch through a detailed mechanistic representation of the major physiological components of the disease. The model explicitly accounts for cholesterol and macrophage trafficking, inflammation, endothelial cell function, oxidative stress, and thrombosis, and has been calibrated to data obtained from multiple sources collected under diverse experimental protocols. In vivo experiments have been conducted in parallel with the modeling efforts in order to enrich the data set available for both calibration and validation. Heterogeneity in the rate of disease progression, consistently seen in the data despite genetic uniformity and experimentally controlled studies, is captured through the development of a simulated mouse cohort. The cohort, consisting of many uniquely parameterized, individual, simulated mice, explores the role of biological uncertainty while meeting top- down constraints derived from in vivo experimental data. In addition to the baseline progression of atherosclerosis, the model has been expanded to mechanistically account for the specific effects of cigarette smoke exposure as well as the dynamic response of the system to exposure cessation. We demonstrate the applicability of the model to the problem of experimental design, in which the simulation results are used to define the protocols for follow-up in vivo studies. The data from these new experiments may be of independent biological interest and, ultimately, will also be applied to further enhance the calibration of the model. Overview of the Apoe-/- Mouse PhysioLab® The Apoe-/- Mouse PhysioLab® platform is a large-scale mathematical model that enables simul