Parameter Trajectory Analysis to Identify Treatment Effects of Pharmacological Interventions

The field of medical systems biology aims to advance understanding of molecular mechanisms that drive disease progression and to translate this knowledge into therapies to effectively treat diseases. A challenging task is the investigation of long-term effects of a (pharmacological) treatment, to establish its applicability and to identify potential side effects. We present a new modeling approach, called Analysis of Dynamic Adaptations in Parameter Trajectories (ADAPT), to analyze the long-term effects of a pharmacological intervention. A concept of time-dependent evolution of model parameters is introduced to study the dynamics of molecular adaptations. The progression of these adaptations is predicted by identifying necessary dynamic changes in the model parameters to describe the transition between experimental data obtained during different stages of the treatment. The trajectories provide insight in the affected underlying biological systems and identify the molecular events that should be studied in more detail to unravel the mechanistic basis of treatment outcome. Modulating effects caused by interactions with the proteome and transcriptome levels, which are often less well understood, can be captured by the time-dependent descriptions of the parameters. ADAPT was employed to identify metabolic adaptations induced upon pharmacological activation of the liver X receptor (LXR), a potential drug target to treat or prevent atherosclerosis. The trajectories were investigated to study the cascade of adaptations. This provided a counter-intuitive insight concerning the function of scavenger receptor class B1 (SR-B1), a receptor that facilitates the hepatic uptake of cholesterol. Although activation of LXR promotes cholesterol efflux and -excretion, our computational analysis showed that the hepatic capacity to clear cholesterol was reduced upon prolonged treatment. This prediction was confirmed experimentally by immunoblotting measurements of SR-B1 in hepatic membranes. Next to the identification of potential unwanted side effects, we demonstrate how ADAPT can be used to design new target interventions to prevent these.Author Summary: A driving ambition of medical systems biology is to advance our understanding of molecular processes that drive the progression of complex diseases such as Type 2 Diabetes and cardiovascular disease. This insight is essential to enable the development of therapies to effectively treat diseases. A challenging task is to investigate the long-term effects of a treatment, in order to establish its applicability and to identify potential side effects. As such, there is a growing need for novel approaches to support this research. Here, we present a new computational approach to identify treatment effects. We make use of a computational model of the biological system. The model is used to describe the experimental data obtained during different stages of the treatment. To incorporate the long-term/progressive adaptations in the system, induced by changes in gene and protein expression, the model is iteratively updated. The approach was employed to identify metabolic adaptations induced by a potential anti-atherosclerotic and anti-diabetic drug target. Our approach identifies the molecular events that should be studied in more detail to establish the mechanistic basis of treatment outcome. New biological insight was obtained concerning the metabolism of cholesterol, which was in turn experimentally validated.