2 nd International Conference on Metabolomics & Systems Biology Systems medicine and metabolic profiling of diseases April 8, 2013 Natal van Riel Eindhoven University of Technology, the Netherlands Dept. of Biomedical Engineering, [email protected]Systems Biology and Metabolic Diseases
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Systems medicine and metabolic profiling of diseases
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2nd International Conference on Metabolomics & Systems Biology
Systems medicine and metabolic profiling of diseasesApril 8, 2013
Natal van Riel
Eindhoven University of Technology, the NetherlandsDept. of Biomedical Engineering, [email protected] Systems Biology and Metabolic Diseases
/ biomedical engineering 12-04-2023
Systems Medicine
PAGE 2
• ‘Systems Medicine involves the implementation of systems biology approaches in medical concepts, research and practice, through iterative and reciprocal feedback between data-driven computational and mathematical models as well as model-driven translational and clinical investigations and practice’EC Coordinating Action Systems Medicine – CASyM
• Understanding disease pathways / networks• Personalized Healthcare / Medicine
• biomarkers• patient specific intervention• guide drug discovery
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Metabolic profiling of diseases
• Metabolome: • current physiological state• interaction of the genotype
with the environment• clinical diagnostics
• Metabolic networks:• structured information about how metabolites
and reactions are interconnected and organized into pathways
• Data integration concept:• metabolomics (metabolite profile)• mathematical models of metabolic networks
PAGE 3
time
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Network-based analysis
Mathematical model
Modeling strategy, depending on type of data and questions
• Constrained genome-wide modeling• stoichiometric model / Genome-Scale Metabolic Models
(GSMM’s) / Constraint-Based Metabolic Models (CBMM)• Recon 2• Thiele et al. 2013, Nat Biotech.• Total number of reactions 7,440• Total number of metabolites 5,063• Number of unique metabolites 2,626
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Cytoscape
http://humanmetabolism.org/
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• Graphs• Stoichiometric matrix N• Mass balances (Differential
Equations)• Steady-state (concentrations constant over time), Nr = 0
a metabolic fingerprint / snapshot
Metabolic Balancing Analysis
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0v 1v
0v1v
2v
0v1v
2v
3v
1v
2v
3v1v
2v
System of algebraic equations
An underdetermined system
Measurements to constrain the underdetermined system
Isotopic tracers, e.g. 13C
Flux space
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Fluxes in Metabolic Networks
• Flexibility and variability in metabolic flux
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Two equivalent routes for converting an input substrate into an output metabolite
If we know/assume that the system aims for minimization of total intracellular fluxes, both routes are not equivalent
If the objective is to maximize ATP yield then also only one route will be utilized
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Flux Balance Analysis
• Assume the homeostatic behavior of the metabolic system somehow reflects an optimal situation
• Introduce a mathematical objective function, for example • minimization of total intracellular fluxes• maximizing ATP production • maximizing the production of a particular metabolite• minimizing nutrient uptake• …
• Optimizing (solving) the under-determined set of algebraic equations can be done by linear programming
• Flux distribution• Visualization
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COnstraints Based Reconstruction and Analysis (COBRA) Toolbox for Matlab, http://opencobra.sourceforge.net
http://sbml.org
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Conclusions (1)
Advantages:• Genome-wide, especially good coverage of
small, monomeric molecules and central metabolism
• Comprehensive network topology (wiring)
• Describes fluxes• Possible to integrate multivariate
data
Limitations:• Qualitative / semi-quantitative• Weak in polymeric metabolites with large heterogeneity, e.g., lipids,
lipoproteins
PAGE 8
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Profiling lipids and lipoproteins
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Lipoprotein metabolism
• 3 types of lipoproteins• Chylomicrons• Very low density lipoproteins
(VLDL), apoB• High density lipoproteins (HDL),
apoA• A continuum of particles of
different size, different composition of TG, cholesterol and CE