herzel.ppt - world technology evaluation center: welcome
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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