Institute for Theoretical Biology
Peter Hammerstein – Evolution Organismic Systems
Andreas V. M. Herz - Computational Neur...
Institute for Theoretical Biology
Teaching (100 & 25 students in biology & biophysics)
Basic courses:
Mathematics & Statis...
Modeling Signaling Cascades
and Gene Regulation
Nils Blüthgen, Szymon Kielbasa, Branka Cajavec, Maciej
Swat, Sabine Becker...
Current Research Projects
●
RAS signaling cascades, target genes,
promoter analysis, DNA methylation
●
Circadian clock: mo...
Each reaction modeled by mass-action kinetics:
E + S ES E + P
Michaelis-Menten kinetics problematic due to
similar concent...
Overexpression of Erk: Sustained Oscillations
physiologically relevant?
circadian clocks, cell cycle, Hes1 somite oscillat...
Oscillations after 1 h RAS induction?
Timescale of days hints to transcriptional feedback:
MKPs?
?
customized RAS target cDNA array : 293 genes (3 spots/gene)
Currently: Identifying negative feeback loops
microarray time ...
Light synchronizes
the clock
Regulation of
physiology and behavior
Clock genes
(e.g. Period2)
Positive
elements
activation...
Simplified model of the
circadian core oscillator
S. Becker-Weimann et al. submitted
Wildtype: simulations reproduce period, amplitudes, phase relations
Per2 mutant (less positive feedback): arythmic
Per2/Cr...
24 48 72 96
Time [hrs]
0
0
1000
2000
3000
Luminescence[units]
120
Data
generation
n = 1
Transfect NIH3T3 fibroblasts
with ...
Huntington Chorea - Gene expression
profiles
and modeling aggregation and
feedbacks
Prolonged polyglutamine stretches in
H...
Modelling of Aggregation in Huntington's
Disease
dx
dt
a b x ,
dy
dt
b x c y z e y ,
dz
dt
c y z d z ,
Nucleation Model
Models for Htt Aggregation (Cont'd)
dx
dt
a b z 1 x ,
dy
dt
b z 1 x c y z e y ,
dz
dt
c y z d z ,
Positive feedback on Htt...
Modeling the G1/S Transition of the Mammalian Cell Cycle
Maciej Swat et al. Proceedings GCB 2003
eee
Simulation Results of G1/S Model
Bistability in the pRB-E2F core
model
Herzel.ppt - World Technology Evaluation Center: Welcome
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Herzel.ppt - World Technology Evaluation Center: Welcome

  1. 1. Institute for Theoretical Biology Peter Hammerstein – Evolution Organismic Systems Andreas V. M. Herz - Computational Neuroscience Hanspeter Herzel - Molecular & Cellular Evolution Junior Research Groups: Laurenz Wiskott – Neural Computation Michal Or-Guil – Systems Immunology Richard Kempter – Theoretical Neuroscience
  2. 2. Institute for Theoretical Biology Teaching (100 & 25 students in biology & biophysics) Basic courses: Mathematics & Statistics for Biologists Theoretical Biology A (Modeling), B (Evolution) Advanced courses: Computational Neuroscience I-IV, Data Analysis, Nonlinear Dynamics, Bioinformatics, Evolutionary Game Theory, Theoretical Immunology etc. (lectures, computer exercises, seminars)
  3. 3. Modeling Signaling Cascades and Gene Regulation Nils Blüthgen, Szymon Kielbasa, Branka Cajavec, Maciej Swat, Sabine Becker-Weimann, Matthias Futschik, Didier Gonze, Samuel Bernard, Hanspeter Herzel Institute for Theoretical Biology, Humboldt-Universität Berlin Major collaborators: Christine Sers, Reinhold Schäfer, Achim Kramer, Erich Wanker Charite Berlin, MDC Support: BMBF Networks: Proteomics & Systems Biology, SFB Theoretical Biology (Projects A3, A4, A5), Stifterverband, GK Dynamics and Evolution
  4. 4. Current Research Projects ● RAS signaling cascades, target genes, promoter analysis, DNA methylation ● Circadian clock: modeling the mammalian core oscillator, synchronization ● Huntington disease: DNA-arrays, protein interaction networks, modeling aggregation and feedback loops
  5. 5. Each reaction modeled by mass-action kinetics: E + S ES E + P Michaelis-Menten kinetics problematic due to similar concentrations of substrates and enzymes Translate into ordinary differential equations: d[S]/dt = - k1 [S][E] + k2 [SE] 13 equations and about 40 parameters Model of Raf/Mek/Erk Signaling Cascade
  6. 6. Overexpression of Erk: Sustained Oscillations physiologically relevant? circadian clocks, cell cycle, Hes1 somite oscillator
  7. 7. Oscillations after 1 h RAS induction? Timescale of days hints to transcriptional feedback: MKPs? ?
  8. 8. customized RAS target cDNA array : 293 genes (3 spots/gene) Currently: Identifying negative feeback loops microarray time series + RNAi for identification of feedback loops Zuber,J., ..., Schä fer,R. (2000). Nature Genetics 24, 144-152.  
  9. 9. Light synchronizes the clock Regulation of physiology and behavior Clock genes (e.g. Period2) Positive elements activation nucleus SCN-neuron Negative elements inhibition Synchronization of peripheral clocks The system
  10. 10. Simplified model of the circadian core oscillator S. Becker-Weimann et al. submitted
  11. 11. Wildtype: simulations reproduce period, amplitudes, phase relations Per2 mutant (less positive feedback): arythmic Per2/Cry2 double knock-out: rescue of oscillations Comparison with experimental observations
  12. 12. 24 48 72 96 Time [hrs] 0 0 1000 2000 3000 Luminescence[units] 120 Data generation n = 1 Transfect NIH3T3 fibroblasts with reporter construct Synchronize cells by inducing growth arrest Induce circadian oscillation by serum shock or forskolin Culture cells with luciferase substrate Continuously measure luminescence Per1 E-box_luc Bmal1_luc Circadian oscillation of fibroblasts can be monitored in living cells Experiments in Kramer Lab (Charite)
  13. 13. Huntington Chorea - Gene expression profiles and modeling aggregation and feedbacks Prolonged polyglutamine stretches in Huntingtin lead to aggregate formation (“nucleation” via positive feedback) Feedbacks via transcription factors, caspases, proteasome inhibition Work in progress: Analysis of hybridized Affymetrics chips Hybridization of cDNA microarray chip Monitoring influence of aggregate formation on gene expression Modelling of aggregate formation and feedback loops
  14. 14. Modelling of Aggregation in Huntington's Disease dx dt a b x , dy dt b x c y z e y , dz dt c y z d z , Nucleation Model
  15. 15. Models for Htt Aggregation (Cont'd) dx dt a b z 1 x , dy dt b z 1 x c y z e y , dz dt c y z d z , Positive feedback on Htt cleavage
  16. 16. Modeling the G1/S Transition of the Mammalian Cell Cycle Maciej Swat et al. Proceedings GCB 2003
  17. 17. eee Simulation Results of G1/S Model Bistability in the pRB-E2F core model

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