1 / 21

HUMBOLDT UNIVERSITY BERLIN

HUMBOLDT UNIVERSITY BERLIN. Institute of Biology. Theoretical biophysics (1992 - ). Theoretical biology (1996 - ). Graduate School „Dynamics of Cellular Processes“ (DFG 1997) Heinrich. Humboldt University. Free University. Max-Planck-Institute of Molecular Genetics. Max-Delbrück-Center.

vine
Download Presentation

HUMBOLDT UNIVERSITY BERLIN

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. HUMBOLDT UNIVERSITY BERLIN Institute of Biology Theoretical biophysics (1992 - ) Theoretical biology (1996 - ) Graduate School „Dynamics of Cellular Processes“ (DFG 1997) Heinrich Humboldt University Free University Max-Planck-Institute of Molecular Genetics Max-Delbrück-Center Hahn-Meitner-Institute

  2. HUMBOLDT UNIVERSITY BERLIN Institute of Biology Theoretical biophysics (1992 - ) Theoretical biology (1996 - ) Graduate School „Dynamics of Cellular Processes“ (DFG 1997) Heinrich SFB „Theoretical Biology“ (DFG 2002) Hammerstein German Systems Biology Project (BMBF 2004) Holzhütter

  3. EDUCATION Curriculum for Biophysics: ~20 Students/year (Biology ~140/year) Diplom and PhD: Experimental or Theoretical lectures and seminars on Systems Biology, 4h/week, computer course: mathematical modeling of biological systems, etc. monograph: The regulation of cellular systems (New York, 1996)

  4. EDUCATION Curriculum for Biophysics: ~20 Students/year (Biology ~140/year) Diplom and PhD: Experimental or Theoretical Graduate school: 15 PhD students, courses, seminars, lectures Workshops International Collaboration of the Graduate School with Boston Bioinformatics program (NSF, DeLisi, T. Smith), Kyoto Genomic and Bioinfomatics Center (M. Kanehisa), 4 joint workshops (2001, 2002, 2003, 2004) exchange of PhD students and teachers International Collaboration with BioCentrum Amsterdam, 3 joint workshops (2001, 2002, 2003) Exchange of PhD students and teachers

  5. Group of Theoretical Biophysics (1 full prof, 1 Juniorprof., 9 PhD, 2 postdoc) MODELLING OF METABOLIC NETWORKS 1974 first comprehensive model of erythrocyte glycolysis 1985 extensions to interaction with membrane transport „Metabolic-osmotic model“, first attempt to develop a full-cell model Various extensions of the model by other groups until now In parallel: Development of MCA Theoretical concept for identifying key steps in metabolism

  6. Other main research topics mRNA translation Metabolic oscillations (cell-cell communication and synchronization) Ca2+ oscillations and waves Membrane structure, Molecular dynamics Protein translocation across ER membrane Gene expression and cell differentiation (immune cells) Signal transduction pathways (e.g. Wnt-pathway) Vesicular traffic Evolutionary optimization of networks mostly in close cooperation with experimentalists, (biophysics, cell biology and molecular biology)

  7. METHODS Nonlinear differential equation systems Numerical simulations Bifurcation theory Metabolic control analysis Stoichiometric analysis Theory of stochastic processes (simulations with Master equations) Optimization methods, e.g. evolutionary algorithms Graph theory

  8. simulations DYNAMICS STRUCTURE stoichiometry, regulatory couplings, enzyme kinetic parameters,… steady states, transient states, oscillations, switches,… BIOLOGICAL FUNCTION Evolution DESIGN PHYSICAL CONSTRAINTS optimizations

  9. MODELING OF SIGNAL TRANSDUCTION PLoS Biology, 1, 116-132 (2003) with M.Kirschner‘s group HMS + Wnt Destruction cycle Effect of Wnt-stimulation b-CATENIN HIGH

  10. MAIN INPUT DATA OF THE MODEL reference state CONCENTRATIONS total Dsh 100 nM total APC 100 nM total TCF 15 nM total GSK3 50 nM total axin 0.02 nM total b-catenin 35 nM free phosphorylated b-catenin 1 nM DISSOCIATION CONSTANTS binding of GSK3 to (APC.axin) 10 nM binding of APC to axin 50 nM binding of b-catenin to (APC.axin.GSK) 120 nM binding of b-catenin to TCF 30 nM binding of b-catenin to APC 1200 nM FLUXES degradation flux of b-catenin via the proteasome 25 nM/h Share of degradation of b-catenin via unphosphorylated form 1.5 % CHARACTERISTIC TIMES phosphorylation/dephosphorylation of APC and axin 2.5 min GSK3 association/dissociation1 min Axin degradation 6 min starting point for time dependent changes or effects of parameter changes

  11. Parameter estimation -catenin degradation, simulations and comparison with experimental data (Xenopus Oocyte extracts) inhibitionof GSK3 addition of TCF inhibition of GSK3 + TCF effect of dishevelled + dishevelled reference curve reference effect of scaffold axin +axin Time, t (t)

  12. ACTIVE ROLE OF PROTEIN DEGRADATION IN SIGNAL TRANSDUCTION fast axin turnover standard case slow axin turnover TRANSIENT STIMULATION OF THE Wnt-PATHWAY Effect of the turnover rate ofthe scaffold axin Amplification and sharpening of the signal synthesis degradation AXIN

  13. DEGRADATION OF AXIN IS A POSSIBLE DRUG TARGET Effect of a loss of APC can be reversed by inhibition of axin degradation APC/axin axin APC concentration of inhibitor necessary to reduce β-catenin to its normal level after loss of APC

  14. KINASE NETWORK with G-proteins

  15. STABILITY, AMPLIFICATION AND DAMPENING FOR ALL POSSIBLE KINASE / PHOSPHATASE NETWORKS OF VARIOUS SIZE B.Binder and R. Heinrich A. (2004), Genome Informatics, 15, 13-23. ~500 kinases dampening 9364 PHOSPHATASE ACTIVITY different pathways 199 amplification unstable UNSPECIFICITY

  16. Plans for the future: Extension of the Wnt-pathway model, HFSP-Project with Harvard Medical School (M.Kirschner) and Hebrew University (Y.Neriah)

  17. Plans for the future: Evolutionary Design of metabolic networks and Signal Transduction networks B A C 1. Systematic network expansion D B Is the evolutionary history of cellular networks encoded in their contemporary structure? A C 2. D B E KEGG-Database: ~5200 reactions ~4500 metabolites A F C 3. etc.

  18. Systematic network expansion “Scope” of metabolites Set of components which can be reach by expanding the network from a single compound 3’-phosphoadenosine 5’phosphosulfate (PAPS) and 3 related compounds 2042 ATP GTP… 1545

  19. Plans for the future: Modeling of vesicular traffic Networks in space 1.0 SNAREs in compartments stable 0.8 0.6 unstable stable 0.4 uniform distribution non-uniform distribution 0.2 stable 0 10 100 1000 1

  20. Plans for the future: networks in space SNARE x SNARE y budding Coat A forward-fusion back-fusion budding Coat B forward-fusion 1 (ER) 2 (Golgi) back-fusion Coat A (COPI) budding Coat A forward-fusion back-fusion budding Coat B forward-fusion back-fusion Coat B (COPII)

  21. MAIN GOALS Understanding the dynamics of cell division and cell differentiation Identification of drug targets Understanding the interrelations of gene expression and network dynamics Understanding the design of cellular networks as outcome of evolution

More Related