References of "Martins Conde, Patricia 50008598"
     in
Bookmark and Share    
See detailMODELING HUMAN METABOLISM: A DYNAMIC MULTI-TISSUE APPROACH
Martins Conde, Patricia UL

Doctoral thesis (2019)

Despite significant advances in constraint-based modelling, a methodology for modelling dynamic multi-tissue models of human metabolism is still missing. Additionally, prior to analysing diseased models ... [more ▼]

Despite significant advances in constraint-based modelling, a methodology for modelling dynamic multi-tissue models of human metabolism is still missing. Additionally, prior to analysing diseased models, it is important to develop a good methodology, as it would not only enable us to capture the effects of metabolism-associated diseases, but it would also allow us to recapitulate known physiological healthy properties of human metabolism. Therefore, a dynamic multi-tissue model using a new methodology was developed. The objective function comprises a set of complex functions that the multi-tissue model needs to perform. To demonstrate the capabilities of this new approach, different healthy, and unhealthy conditions were simulated. In a first step, the effect of different healthy conditions was analysed (i.e. the fasting, the ingestion of different meals, and exercising at various intensities, and conditions), demonstrating the model’s capability to correctly predict metabolic changes occurring on energy-associated pathways. In the second step, biomarkers for a range of inborn errors of metabolism were predicted, and the predictions were shown to be in good agreement with previous data. Finally, after verifying the capability of the dynamic multi-tissue model to review known physiological aspects of human metabolism, this model was further integrated with a physiologically- based pharmacokinetic model of glucose metabolism, previously developed by Schaller et al. (2013). Contrasting conditions, such as healthy and diabetic, were simulated using the multi-scale model during fasting and after an oral glucose tolerance test and candidate drugs to treat type 2 diabetes mellitus were predicted. Five out of the 80 simulated drug targets were predicted as candidate anti-diabetic targets, and the majority of drugs known to inhibit the predicted drug targets, have already been shown to have anti-diabetic effects. The developed approach can be applied to any metabolic disease and to any system where homeostasis plays an important role, or where a simple biomass optimization function is not applicable. Furthermore, the large amount of data collected for the multi-tissue model generation is of significant value for tissue constraint-based metabolic modellers who need data to constrain their models. [less ▲]

Detailed reference viewed: 66 (16 UL)
Full Text
Peer Reviewed
See detailConstraint based modelling going multicellular
Martins Conde, Patricia UL; Sauter, Thomas UL; Pfau, Thomas UL

in Frontiers in Molecular Biosciences (2016), 3(3),

Constraint based modelling has seen applications in many microorganisms. For example, there are now established methods to determine potential genetic modifications and external interventions to increase ... [more ▼]

Constraint based modelling has seen applications in many microorganisms. For example, there are now established methods to determine potential genetic modifications and external interventions to increase the efficiency of microbial strains in chemical production pipelines. In addition, multiple models of multicellular organisms have been created including plants and humans. While initially the focus here was on modelling individual cell types of the multicellular organism, this focus recently started to switch. Models of microbial communities, as well as multitissue models of higher organisms have been constructed. These models thereby can include different parts of a plant, like root, stem or different tissue types in the same organ. Such models can elucidate details of the interplay between symbiotic organisms, as well as the concerted efforts of multiple tissues and can be applied to analyse the effects of drugs or mutations on a more systemic level. In this review we give an overview of the recent development of multi-tissue models using constraint based techniques and the methods employed when investigating these models. We further highlight advances in combining constraint based models with dynamic and regulatory information and give an overview of these types of hybrid or multi-level approaches. [less ▲]

Detailed reference viewed: 214 (18 UL)