network 1 ursula klingmüller regenerating hepatocytes - a systems biology approach coordinator: hd...
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Network 1Ursula Klingmüller
Regenerating Hepatocytes - a Systems Biology Approach
Coordinator:HD Dr. Jens TimmerCenter for Data Analysis and ModelingCenter for Systems BiologyDepartment for Mathematics and PhysicsUniversity of Freiburg
Deputy-Coordinator:PD Dr. Ursula KlingmüllerTheodor-Boveri-Group Systems Biology of Signal TransductionGerman Cancer Research Center (DKFZ)Heidelberg
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BMBF-Funding Initiative: Systems of Life - Systems Biology
Ursula Klingmüller
Platform Modeling
Platform Cell Biology
Network 1Regeneration
Network 2Detoxificationand Dedifferentiation
Networks: regionally Platforms: nationwide
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AimUrsula Klingmüller
Systems Properties of Hepatocytes
Determination of Conditions for in vitro Propagation and Differentiation of Hepatocytes
Hepatocyte Cell Line
Network 1Regeneration
Platform Modeling
Platform Cell Biology
Network 2Detoxificationand Dedifferentiation
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Systems Biology of Regenerating HepatocytesUrsula Klingmüller
Data-based Mathematical Modeling of Signaling Pathways Involved in Hepatocyte Regeneration
Systems Properties of Regenerating Hepatocytes
Platform Modeling
Platform Cell Biology
Network 2Detoxificationand Dedifferentiation
Network 1Regeneration
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Regeneration of HepatocytesUrsula Klingmüller
Highly Regulated Growth Process
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Consortium:Freiburg/Heidelberg/Tübingen/Würzburg
Ursula Klingmüller
Hepatocytesvon Weizsäcker
ModelingTimmer
Signaling Pathways1. Klingmüller
2. Walz/Merford/Sparna
3. Mohr
5. Borner
6. Klingmüller
Transcription Factors7. Schütz/Nordheim
Transcription Factors8. Donauer/Walz
8
4. Hecht
Catenin
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Progress: Standard Operating Procedures (SOPs)
Ursula Klingmüller
Cultivation of Primary Hepatocytes:• Defined Medium• Starving Procedure
Preparation of Primary Hepatocytes by Collagenase Perfusion:• C57/BL6 mice• 6-8 weeks old• male
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Success Story:Data-based Modeling of the JAK-STAT Pathway
Ursula Klingmüller
collaboration with the group of HD Dr. J. Timmer
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Model 1:Feed Forward Cascade
Ursula Klingmüller
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Model 2:Cycling
Ursula Klingmüller
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Hypothesis Testing:Mathematical Modeling of Quantitative Data
Ursula Klingmüller
Model 1 Model 2
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In Silico Prediction:Unobservable Components
Ursula Klingmüller
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In Silico Prediction:Targets for Efficient Perturbation
Ursula Klingmüller
Transcriptional Yield
Setting k4 = 0 or =
One cylce yields only 45% efficiency
Most sensitive to nuclear shuttling parameters
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Experimental Validation of PredictionUrsula Klingmüller
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New Knowledge Generated:JAK-STAT Pathway „Remote Sensor“
Ursula Klingmüller
PNAS 100, 2003, 1028-1033
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New Knowledge Generated:JAK-STAT Pathway „Remote Sensor“
Ursula Klingmüller
Continuous monitoring of receptor activity
Optimal use of limited STAT5 pool
PNAS 100, 2003, 1028-1033
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The Challenge:Quantitative Time/Space Resolved Data
Ursula Klingmüller
Purification by Anti-EpoRImmunoprecipitation
ImmunoblotAnti-EpoR
pEpoR
Quantitative Immunoblotting
0 2 4 6 108 121 2014 16 4030 50 6018 26 2822+ Epo
Quantitative Proteinarray
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Summary - VisionUrsula Klingmüller
Modular data-based models of signaling pathways involved in hepatocyte regeneration
Incorporation of cross-talk
Generation of interconnected “big“ model
Identification of conditions for in vitro expansion and differentiation of hepatocytes