Integration of Probabilistic Regulatory Networks into Constraint-based Models of Metabolism with Applications to Alzheimer's Disease

Background: Mathematical models of biological networks can provide important predictions and insights into complex disease. Constraint-based models of cellular metabolism and probabilistic models of gene regulatory networks are two distinct areas that have progressed rapidly in parallel over the past decade. In principle, gene regulatory networks and metabolic networks underly the same complex phenotypes and diseases. However, systematic integration of these two model systems remains a fundamental challenge.

Results: In this work, we address this challenge by fusing probabilistic models of gene regulatory networks into constraint-based models of metabolism. The novel approach utilizes probabilistic reasoning in BN models of regulatory networks serves as the "glue" that enables a natural interface between the two systems. Probabilistic reasoning is used to predict and quantify system-wide effects of perturbation to the regulatory network in the form of constraints for flux variability analysis. In this setting, both regulatory and metabolic networks inherently account for uncertainty. Applications leverage constraint-based metabolic models of brain metabolism and gene regulatory networks parameterized by gene expression data from the hippocampus to investigate the role of the HIF-1 pathway in Alzheimer's disease. Integrated models support HIF-1A as effective target to reduce the effects of hypoxia in Alzheimer's disease. However, HIF-1A activation is far less effective in shifting metabolism when compared to brain metabolism in healthy controls.

Conclusions: The direct integration of probabilistic regulatory networks into constraint-based models of metabolism provides novel insights into how perturbations in the regulatory network may influence metabolic states. Predictive modeling of enzymatic activity can be facilitated using probabilistic reasoning, thereby extending the predictive capacity of the network. This framework for model integration is generalizable to other systems.