Slideshare uses cookies to improve functionality and performance, and to provide you with relevant advertising. If you continue browsing the site, you agree to the use of cookies on this website. See our User Agreement and Privacy Policy.

Slideshare uses cookies to improve functionality and performance, and to provide you with relevant advertising. If you continue browsing the site, you agree to the use of cookies on this website. See our Privacy Policy and User Agreement for details.

Successfully reported this slideshow.

Like this presentation? Why not share!

- ChEBI and genome scale metabolic re... by Neil Swainston 1369 views
- Download ebook systems biology cons... by martinezarthur 110 views
- Randomizing genome-scale metabolic ... by Areejit Samal 567 views
- Apo B‐Lipoprotein profile modelling... by yvonne0 689 views
- Minimal and maximal models of gluco... by yvonne0 862 views
- Researching Cancer In the Cloud - U... by Spring by Pivotal 1644 views

1,808 views

Published on

No Downloads

Total views

1,808

On SlideShare

0

From Embeds

0

Number of Embeds

245

Shares

0

Downloads

65

Comments

0

Likes

1

No embeds

No notes for slide

- 1. Metabolic Syndrome workshop Dec. 13, 2013 Eindhoven University of Technology, Eindhoven Natal van Riel Dept. of Biomedical Engineering, TU/e, n.a.w.v.riel@tue.nl Systems Biology and Metabolic Diseases
- 2. Can we link understanding of metabolism and biochemistry (incl. modeling) to the multi-omics data that are collected in in research projects and in the clinic of the (near) future and tendencies towards stratified and personalized health and healthcare / biomedical engineering 16-12-2013 PAGE 2
- 3. Is the time right for application of GSMM‟s …for a Systems Medicine approach of Metabolic Syndrome? 2007 Recon1 (Duarte 2007 PNAS 104(6): 1777) 2010 Hepatonet (Gille 2010 Mol Syst Biol 6:411) 2013 Recon2 (Thiele et al. 2013, Nat Biotech.) / biomedical engineering 12/16/2013 PAGE 3
- 4. Recon 2 • Genome-Scale Metabolic Model • Total number of reactions 7,440 • Total number of metabolites 5,063 • Number of unique metabolites 2,626 http://humanmetabolism.org/ / biomedical engineering 16-12-2013 PAGE 4
- 5. Genome-scale metabolic reconstructions Advantages: • Especially good coverage of small, monomeric molecules and central metabolism • Comprehensive network topology (wiring) Limitations: • Manual curration needed of many pathways outside central metabolism • Weak in polymeric metabolites with large heterogeneity, e.g., lipids, lipoproteins / biomedical engineering 12/16/2013 PAGE 5
- 6. Applications of the global human metabolic network “Genome-scale metabolic network reconstructions provide a platform to interpret omics data in a biochemically meaningful manner.” • Four classes of application: 1. Integration of „omics‟ data for tissue and cell specific network reconstruction, 2. Mapping homologous genes for global mammalian network reconstruction, 3. Contextualization of „omics‟ data from pathological and drug-treated states, 4. Simulation of pathological and drug-treated states / biomedical engineering 16-12-2013 PAGE 6
- 7. Example: a metabolic perspective on ADHD, autism • Neurotransmission is disrupted in most psychiatric disorders • Serotonergic system malfunctioning • An underlying metabolic cause Yap,et al 2010, J Proteome Res 9(6): 2996 / biomedical engineering 16-12-2013 PAGE 7
- 8. Metabolomics of 24 hour urine • Metabolomics (N=362) • Analysis and interpretation with network model • Recon2, curated for tryptophan metabolism Dermois et al / biomedical engineering 12/16/2013 PAGE 8
- 9. HUMETICS HUman METabolic diagnostICS Network-based analysis APeT in collaboration with TU/e Dermois, van den Eijnde et al / biomedical engineering 16-12-2013 PAGE 9
- 10. Integration of multi-omics data (A) Gene expression pattern (4 clusters) (B) Metabolic network expression overlay / biomedical engineering 16-12-2013 PAGE 10
- 11. Zelezniak et al, 2010, PLoS Comput Biol 6(4): e1000729. / biomedical engineering 16-12-2013 PAGE 11
- 12. Simulation / biomedical engineering 16-12-2013 PAGE 12
- 13. COnstraints Based Reconstruction and Analysis (COBRA) methods • So far, just the topology • What about fluxes • Flux Balance Analysis (FBA) • Flux Variability Analysis (FVA) • … / biomedical engineering 16-12-2013 PAGE 13
- 14. Network stoichiometry and Stoichiometric Matrix • A hypothetical network • Stoichiometry matrix • Stoichiometric model d s (t ) N v ( s ( t )) dt with the species concentrations collated in a vector s and the reaction rates in a vector v [ v1 , ..., v 5 ]T / biomedical engineering 16-12-2013 PAGE 14 [ s1 , ..., s 4 ] T
- 15. Steady-state („homeostasis‟) d s (t ) N v ( s ( t )) ˆ 0 dt Nv 0 metabolite balancing equation • Set of differential equations set of algebraic equations with the rates in v unknown 1 1 1 0 0 1 1 0 1 1 0 0 0 0 0 0 0 0 1 1 v1 v2 v3 v4 v5 0 0 0 0 • Here 4 equations (4 species) and 5 unknowns • an under-determined set of equations • not a single solution / biomedical engineering 16-12-2013 PAGE 15
- 16. Metabolic Balancing Analysis • Mass balances (Differential Equations) • Steady-state (concentrations constant over time), (N v = 0) • A metabolic fingerprint / snapshot v0 Flux space v1 v1 System of algebraic equations v2 v0 v2 An underdetermined system v1 v2 v1 v0 v2 v3 v3 v1 • Measurements to constrain the underdetermined system • Isotopic tracers, e.g. 13C • Solve / simulate with Flux Balance Analysis / biomedical engineering 16-12-2013 PAGE 16
- 17. Analyzing pathway diagrams Two equivalent routes for converting an input substrate into an output metabolite If we know/assume that the system aims for minimization of total (number of) intracellular fluxes (efficiency), both routes are not equivalent If the objective is to maximize ATP yield then also only one route will be utilized • Can be linked to an objective function to be minimized or maximized in FBA / biomedical engineering 16-12-2013 PAGE 17
- 18. The conceptual basis of Flux Balance Analysis With no constraints, the flux distribution of a biological network may lie at any point in a solution space Through optimization of an objective function, FBA can identify a single optimal flux distribution that lies on the edge of the allowable solution space N mass balance constraints imposed by the stoichiometric matrix N + capacity constraints imposed by the lower and upper bounds (ai and bi) are applied to a network an allowable solution space The network may acquire any flux distribution within this space, but points outside this space are denied by the constraints Orth et al. Nat Biotechnol. 2010; 28(3): 245-248 / biomedical engineering 16-12-2013 PAGE 18
- 19. A multi-tissue type genome-scale metabolic network • Implications for blood-based metabolic biomarkers Bordbar, et al., I. (2011) BMC Syst. Biol., 5, 180 / biomedical engineering 16-12-2013 PAGE 19
- 20. Systems medicine and metabolic modelling Mardinoglu & Nielsen. J Intern Med 2012; 271:142–154 / biomedical engineering 16-12-2013 PAGE 20
- 21. Systems medicine and metabolic modelling / biomedical engineering 16-12-2013 PAGE 21
- 22. / biomedical engineering 16-12-2013 PAGE 22

No public clipboards found for this slide

Be the first to comment