Institute for Theoretical Biology

Peter Hammerstein – Evolution Organismic SystemsAndreas V. M. Herz - Computational Neuroscience Hanspeter Herzel - Molecular & Cellular Evolution

Junior Research Groups:Laurenz Wiskott – Neural ComputationMichal Or-Guil – Systems ImmunologyRichard Kempter – Theoretical Neuroscience

Institute for Theoretical Biology

Teaching (100 & 25 students in biology & biophysics)

Basic courses:Mathematics & Statistics for BiologistsTheoretical 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)

Modeling Signaling Cascades and Gene Regulation

Nils Blüthgen, Szymon Kielbasa, Branka Cajavec, Maciej Swat, Sabine Becker-Weimann, Matthias Futschik, Didier Gonze, Samuel Bernard, Hanspeter HerzelInstitute 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

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

Each reaction modeled by mass-action kinetics:E + S ES E + P

Michaelis-Menten kinetics problematic due tosimilar 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

Overexpression of Erk: Sustained Oscillations

physiologically relevant?circadian clocks, cell cycle, Hes1 somite oscillator

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 series + RNAi for identification of feedback loops

Zuber,J., ..., Schäfer,R. (2000). Nature Genetics 24, 144-152. 

Light synchronizesthe clock

Regulation ofphysiology and behavior

Clock genes(e.g. Period2)

Positiveelements

activation

nucleus

SCN-neuron

Negativeelements

inhibition

Synchronization ofperipheral clocks

The system

Simplified model of thecircadian core oscillator

S. Becker-Weimann et al. submitted

Wildtype: simulations reproduce period, amplitudes, phase relationsPer2 mutant (less positive feedback): arythmicPer2/Cry2 double knock-out: rescue of oscillations

Comparison with experimental observations

24 48 72 96

Time [hrs]

0

0

1000

2000

3000

Lum

ines

cenc

e [u

nits

]

120

Datageneration

n = 1

Transfect NIH3T3 fibroblastswith reporter construct

Synchronize cells by inducinggrowth arrest

Induce circadian oscillation byserum shock or forskolin

Culture cells with luciferase substrate

Continuously measure luminescence

Per1 E-box_lucBmal1_luc

Circadian oscillation of fibroblasts

can be monitored in living cells

Experiments in Kramer Lab (Charite)

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

Modelling of Aggregation in Huntington's Disease

dxdt

a b x ,

dydt

b x c y z e y ,

dzdt

c y z d z ,

Nucleation Model

Models for Htt Aggregation (Cont'd)

dxdt

a b z 1 x ,

dydt

b z 1 x c y z e y ,

dzdt

c y z d z ,

Positive feedback on Htt cleavage

Modeling the G1/S Transition of the Mammalian Cell Cycle

Maciej Swat et al. Proceedings GCB 2003

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Simulation Results of G1/S Model

Bistability in the pRB-E2F core model