Multiscale Modelling of the Bile Acid and Xenobiotic System

The bile acid and xenobiotic system (BAXS) defines an intricate physiological network of chemoprotective and transporter-related functions that ensure the detoxification and removal from the body of harmful xenobiotic and endobiotic compounds while ensuring that primary bile acids (essential for the emulsification and absorption of dietary fats and fat-soluble vitamins) are not eliminated and can be re-used. The overall metabolic flux of the BAXS is primarily achieved through the activities of nuclear receptors, which have the ability to directly bind to DNA and regulate gene expression. Nuclear receptors can be thought of as metabolic sensors of exogenous and endogenous toxins and a detailed knowledge of the factors that govern their activity has critical implications to a range of physiological processes such as drug-drug interactions, intracrine hormone metabolism, xenobiotic clearance and cholesterol/lipid homeostasis.

The BAXS involves the coordinated activities of many genes across multiple temporal and spatial scales. Basic BAXS processes and their time scales include the binding of ligands to nuclear receptors (hours), gene expression and regulation (hours), transporter protein (minutes) and metabolic enzyme activity (seconds). Spatially, BAXS components range from molecules (e.g., nuclear receptors) to organs (e.g., liver). Given the complex multiscale nature the BAXS, it is difficult to assess the exact importance and impact of individual receptors and their activating/deactivating ligands with respect to the overall BAXS flux and how it can vary throughout a number of participating organ systems. A comprehensive description of the interacting components that govern BAXS gene expression would enable the identification of regulatory "nodes" as targets for treatment regimes, and understanding of the components impacting drug-drug interactions, and provide a framework for the design of large-scale, integrated prediction studies.

The aim of this application is to explore and develop novel modelling and simulation techniques facilitating a multiscale characterization of the BAXS.

Conceptually, we adopt a bottom-up multiscale systems biology approach, aiming to derive system behavior on higher spatial or temporal scales from the dynamics and interactions of BAXS model components at lower, more detailed scales. The coarse graining that connects the different scales involves identifying which types of collective behavior on a fundamental scale give rise to a coherent phenomenon on a higher scale. The great disadvantage of bottom-up models, namely the requirement to invest much care into the construction of the fundamental modelling layer, is at the same time their main advantage: the process of assembling the model unveils gaps in our knowledge and points out new directions for experimental studies that without the modelling effort would be less apparent. Another problem with the bottom-up multiscale approach in systems biology is the lack of sufficient data.  Because of this, we will initially develop reference models manually, based on information from the literature, and concentrate on the exploration, evaluation and development suitable multiscale modelling methodology and technology.