Berlin

Supply with Hepatocytes

• Group of Prof. Nüssler (Platform Cell Biology): Supply of the Network Detoxification and Dedifferentiation with human hepatocytes.

Holzhütter - Zeilinger

• Subject: Flux-analysis in the amino acid metabolism of hepatocytes
  Details: Data on the time-dependent kinetics of 18 amino acids, ammonia and urea from several runs of the 3D liver cell bioreactor were delivered to Dr. Guthke (Platform Cell Biology, Jena) and Prof. Holzhütter. In a first step, these data were analysed in the group of Dr. Guthke by means of a phenomenological two-compartment model consisting of a system of 42 differential equations. It is now planned to analyse the data on the basis of the flux-balance model of the complete hepatocyte metabolism developed in the group of Prof. Holzhütter.

Herrmann - Frey

• Subject: Membrane Biochemistry and Transporters
  Details: Scientific exchange about lateral diffusion in lipid bilayers and transmembrane transporter activity. In the near future, Prof. Herrmann's group will examine the influence of statins on the lipid trafficking in hepatocytes, as well as on the physical properties of the canalicular membrane and the organization of lipids in the bile.

Herrmann - Herzel

• Subject: Mathematical modeling techniques.
  Details: Discussions on the efficient stochastic simulation of a Master equation and the transferability of equilibrium-state simulations to non-equilibrium conditions.

Magdeburg

Central Data Management

• An important goal of the network HepatoSys is the implementation of a joint data management system for all types of data that arise in terms of Systems Biology in the network. This task is realized by the central data management at the MPI Magdeburg. The database for HepatoSys comprises the products Phylosopher and Expressionist of the company Genedata and an additional model block that has been developed newly by Genedata. The database is stored on a database server at the MPI Magdeburg.
  
  Important future developments include: standardization of non high throughput data, development of the corresponding relational data schemes, setup of the relational databases, development of a data- and project management modul which also allows for the access of selected data by the scientific community and furthermore, integration of all components in a joint database environment. As a pilot project 1-dimensional Western blot data that are produced in the network have been standardized and a corresponding relational database is currently being set up.
  
  E-Mail: bannasch(at)mpi-magdeburg.mpg.de
  Phone: +49 391 6110 216
  Link: Central Data Management

Cooperations with HepatoSys Members

• The HepatoSys members cooperate with the central data management of HepatoSys in order to use the Genedata products for the analysis of their data as well as for the storage of their data in the database. Cooperation between the central data management and the HepatoSys members is also necessary
  (1) to solve user problems with the software (user support) and
  (2) to find out which functionalities of the database should be improved or added and what could be the best solution in the opinion of the users (realized via surveys of the database users).

Server

• The database for HepatoSys is stored on a database server at the Max Planck Institute Magdeburg.

Workshop

• A workshop for advanced users of the HepatoSys database was organized by the central data management. It took place on the 7th of May 2007 at the Max Planck Institute Magdeburg. Workshop title: "Integrated database for HepatoSys - Advanced user workshop". Major topics were: (1) possibilities and limits of the data and project management in the HepatoSys database (presented by Genedata), (2) presentation of the experiences of three HepatoSys members who already had performed analyses of their data using Expressionist and/or Phylosopher, (3) presentation of a pre-release of the model block by Genedata.

Mirschel/Gilles - Huard/Gilles

• Subject: Modeling and graphical representation of the cell cycle model
  Details: The visualization component of ProMoT is used to illustrate the cell cycle model. Also intensive discussions about the graphical representation of models is part of this cooperation.

Samaga/Klamt - Huard/Gilles

• Subject: Logical modeling
  Details: Connection of logical models of signaling pathways and cell cycle and analysis using CellNetAnalyzer.

Leipzig

Drasdo - Gebhardt/Zellmer

• Subject: Ammonia and Glutamine Metabolism in single cells
  Details: Integration of Ammonia and Glutamine metabolism into model to study their concentration in blood during the regeneration process within a Sugar grant. This part includes several partners which modelled the ammonia and glutamine metabolism in single cells.

Jena

Workshops

• Group of Prof. Guthke: Workshop serial HepatoSys, March 16, 2007 Data and Knowledge Based Biomolecular Network Reconstruction.

• Group of Prof. Guthke: International Workshop Transcriptome and Proteome Data Analysis and Warehousing towards Systems Biology, June 12-13, 2008. This workshop was focussed on data analysis and warehousing dedicated to post-genomic data such as transcriptome and proteome. Methodologies that permit the measure of genes, proteins or metabolites at a large scale have been developed rapidly. In order to interpret these experimental data and helping to understand cells and organisms not as a group of genes, proteins and metabolites, but instead as complex systems biologists now require quantitative tools. Systems biology aims to understand biological systems at a holistic level by integrating theoretical and experimental research.
  http://www.domchips.org/

• Group of Prof. Guthke: International Workshop Gene Regulatory Network Inference (part of the workshopserial systembiologie.de), September 25-26, 2008. The Workshop was focussed on biomolecular network inference methods based on experimental data and prior knowledge. With the development of high-throughput technologies, such as DNA microarrays, ChIP-on-chip, protein and peptide arrays, scientists are today able to carry out global analyses on the DNA, RNA and protein level. Based on such measurements, systems biology aims to ascertain the dynamic interactions of the components within a living system that make up its functioning profile. A particular topic in systems biology is the deciphering of dynamic gene regulatory networks (GRNs). The inference of GRNs from different types of molecular biological data allows to extract basic hypotheses about biological processes up to their detailed mathematical modeling and systems theoretical analysis. Modeling the physiology of living systems as a whole provides many practical benefits by offering insights into how to control or optimise operations in biotechnology and medicine. The Workshop brought together researchers from the biological and medical profession with those from the bioinformatics and computer science community. Participants had the opportunity to review state-of-the-art applied methods for data and knowledge based network inference. In talks with subsequent discussions the Workshop provided a forum for researchers and developers from the life and the computer sciences to share their views, ideas and visions. It is intended to foster collaboration and progress in systems biology by encouraging the joint use of data and knowledge based methods to elucidate the structure and dynamics of systems in biology and medicine.
  http://www.domchips.org/workshop_Jena_sept2008.htm

Dresden

Conference

• Dresden Conference SBMC 2008, Statusseminar 2008, satellite meetings of project committee, steering committee and systembiologie.de, All members of HepatoSys, 22.-24.05.2008. In the post-genomic era, understanding the molecular basis of complex biological processes requires both new experimental and conceptual approaches. High-throughput analytical methods provide a comprehensive dissection of the regulatory components acting in a biological process in various cellular and model organisms along the evolutionary scale. Novel techniques such as single cell or single molecule imaging provide unprecedented spatial and temporal resolution in quantitative analysis. However, new computational, mathematical, engineering and physical approaches, are needed to integrate such wealth of experimental information and develop theoretical models that can accurately describe the design principles of biological systems and predict their behavior in a patho-physio-logical context. SBMC 2008 presents cuttingedge experimental, theoretical and computational approaches to unravel the design principles underlying a wide range of regulatory processes in mammalian cells, including cell organization, metabolic pathways, genetic and signaling networks, tissue morphogenesis and development, and pathogenetic mechanisms.
  During the statusseminar there is a posterprensentation and several talks of the principal investigators of HepatoSys. The program of the conference is posted on the web site.

Conference

• European Conference on Mathematical and Theoretical Biology (ECMTB) July 18.-22. 2005: organised by the Deutsch group; 800 participants; during the meeting all modeling groups of HepatoSys were present and interacted closely; Prof. Höfer and Dr. Brusch (Network Regeneration, Platform Modeling) presented their results in a Mini-Symposium that had been organised by Dr. Peletier and Prof. Westerhoff; Prof. Timmer (Network Regeneration) together with Prof. Deutsch (Platform Cell Biology), Dr. Kummer and Prof. Gilles (Platform Modeling) organised a Mini-Symposia on 'Parameter identification and model discrimination for cellular systems: methods, tools and applications'.

Hamburg

None

Stuttgart

None

Freiburg

Server

• Development and Implementation of the Data-exchange-server for all members of HepatoSys through Dr. Heisner (Project Management) in August 2005.

Supply with Hepatocytes

• Group of Prof. Timmer (Network Regeneration): Supply of the Network Regeneration with mouse hepatocytes.

Supply with SOPs

• Group of Prof. Timmer (Network Regeneration): Development of the experimental design for fixing the standard operating procedures for primary mouse hepatocytes. Supply for most partners of HepatoSys.

Administration and Organization

• All subsidiary project manager of HepatoSys (Berlin, Stuttgart, Dresden, Dortmund, Freiburg) and Dr. Heisner are working together on administrational and organisational tasks within HepatoSys according to the working packages.

Meetings Network Regeneration

• Group of Prof. Borner (Network Regeneration): Fifth Tuscany Retreat on Cancer Research "Genetic profiling, resistance mechanism and novel treatment concepts in cancer", August 20, 2007. Some surprises from FasL signalling in cultured, primary hepatocytes. Switch from apoptosis to proliferation of primary hepatocytes.

• Peer review of the excellence initiative from the Albrecht-Ludwigs-University, Scientific members of the Freiburg working groups Borner, Nitschke and Timmer as well as the central project management of HepatoSys, June 14-15, 2007, Posterpresentation and interviews about the work within HepatoSys.

• Seminar series "Birth, thrive and death of normaland aberrant cells", Dr. Cristina Munoz-Pinedo, Prof. Dr. Christoph Borner, April 7, 2008, Mitochondria-dependent and -independent pathway of apoptosis.

• Seminar series "Birth, thrive and death of normaland aberrant cells", Dr. Veronique Baud, Prof. Dr. Christoph Borner, June 16, 2008, Novel roles of the non-canonical NF-kB pathway.

• Seminar series "Birth, thrive and death of normaland aberrant cells", PD Dr. Heike Bantel, Prof. Dr. Christoph Borner, July 14, 2008, Role of apoptosis in liver diseases.

Meeting Steering Commitee

• All members of the HepatoSys steering committee, Prof. Timmer, Prof. Hengstler, Dr. Heisner and Dr. Klingmüller from the HepatoSys project committee, Prof. Laplace and Dr. Nimmesgern from the BMBF, Dr. Miczka and Dr. Stüttgen from the PTJ, local and central project management of HepatoSys: Steering committee meeting. April 17-18, 2007, Visit of laboratories and discussion about HepatoSys phase I+II, master milestone plan, overall concept and future activities in Germany and Europe.

Heidelberg

Conference

• International Conference on Systems Biology (ICSB): October 9.-13. 2004 the 5th International Conference on Systems Biology was hosted in Heidelberg/Germany with participation of all working groups of HepatoSys; about 800 international experts from 37 countries presented and discussed their work in numerous poster sessions, workshops, and oral presentations, reaching from microbial systems biology to methods and software, and systems biology for medicine.

Conference

• Conference on Systems Biology of Mammalian Cells (SBMC): July 12-14, 2006 at the Convention Center; promoted by the competence network HepatoSys.

Workshop

• First collaborative workshop of the workshop serial systemsbiology.de at the Bioquant in Heidelberg, Dr. Thomas Maiwald (talk), Dr. Andreas Schuppert (talk), Dr. Ute Heisner (organization), October 16-17, 2007, First collaborative workshop serial of all existing initiatives for systems biology in Germany.

Workshops

• Workshop serial HepatoSys, Dr. Isabel Rojas, May 21-23, 2007, Storage and annotation of reaction kinetics data.

• 4th Workshop on Computation of Biochemical Pathways and Genetic Networks organized by Dr. Kummer (September 12-13, 2005).

• Workshop "Storage and Annotation of Reaction Kinetics Data", Scientific Databases and Visualisation Group (Isabel Rojas), EML Research, Heidelberg, May 21-23, 2007, The main objective of the workshop is to discuss issues regarding the generation, storage, integration, annotation and usage of kinetic data of biochemical reactions in the context of systems biology.
  http://projects.eml.org/sdbv/events/workshop2007/index_html

• Computation of Biochemical Pathways and Genetic Networks (part of the workshopserial systembiologie.de), Dr. Sven Sahle und Prof. Ursula Kummer, Bioquant, Heidelberg, September 22-23, 2008, The workshop was focused on recent methodological developments in computational systems biology. The sessions were model merging, model identification, analysis of stochastic systems and new methods in nonlinear dynamics.
  http://otto.bioquant.uni-heidelberg.de/workshop08

Seminars

• HepatoSys Status seminar 2007 at the DKFZ, All members of HepatoSys, October 15-16, 2007, Postersession, series of lectures of the principal investigators, satellite meetings of project committee and steering committee.

Klingmüller - Muckenthaler

• Subject: Exchange of information on regulation of hepatic growth and iron supply. We planed to identify the role of the BMP/SMAD signalling pathway in hepcidin expression in primary hepatocytes
  Details: We had extensive discussion and plan to cooperate on common experiments later in 2009.

• Subject: TGFbeta sign+G36aling and cell cycle (immunoblotting).
  Details: Development of a data-driven model of TGFbeta signaling and experiments on cell cycle regulation.

• Subject: Quantification and modeling of signal transduction pathways
  Details: Model development, data exchange, testing of theoretical predictions.

Höfer - D'Alessandro

• Subject: Mathematical model
  Details: PI3K mathematical model.

Höfer - Kummer

• Subject: Modeling
  Details: Development of the calcium signal transduction model.

Mannheim

None

Bochum

None

Erlangen

None

Munich, Martinsried

None

Regensburg

None

Duesseldorf

Bode - Schliess

• Subject: Gene expression profiling
  Details: Modulation of IL6-induced gene expression profiles in cultured mouse hepatocytes by IL1beta and cellular dehydration.

Dortmund

Supply with Hepatocytes

• Group of Prof. Hengstler (Platform Regeneration): Establishing network-wide procedures for cultivation of hepatocytes (SOP); establishing conditions for preparation and shipment of frozen hepatocytes, supply of most of the working groups of HepatoSys with cultured mouse-, rat and human hepatocytes.

Workshop

• Workshop serial HepatoSys, Group of Prof. Hengstler (Platform Regeneration), January 26, 2007, SOPs in HepatoSys, Scientific Writing for Dummies.

Tuebingen, Reutlingen

None

Wurzburg

None

Ulm

None

Berlin - Freiburg

Zeilinger - Timmer

• Subject: Public relation
  Details: Providing a functioning bioreactor together with an display dummy to show how an external bioreactor with human hepatocytes is working; collection of these presentation material for the purpose of public relations.

Herzel - Timmer

• Subject: Modeling the TGF-beta/SMAD pathway.
  Details: Joint experimental and modeling work between the groups Klingmuller, Timmer and Herzel. Gene expression arrays for identification of TGF-beta stimulated genes. Investigation of SMAD7 and SnoN as potential feedback mechanisms.

• Subject: modeling and data fits
  Details: Modeling of the G1/S transition of the cell cycle.

Herzel - Bartolome Rodriguez

• Subject: Modeling of MAPK
  Details: Mutual visits and talks.

Westermark/Herzel - Bartolome Rodriguez

• Subject: Modeling of IRS-1
  Details: Mutual visits and talks.

von Weizsäcker - Borner

• Subject: Apoptosis in primary mouse hepatocytes
  Details: Hepatocyte supply and optimizing culture conditions for studying apoptosis in primary mouse hepatocytes.

• Subject: Isolation of primary mouse hepatocytes.
  Details: The group isolates hepatocytes from mice with different genotypes.

von Weizsäcker - Merfort

• Subject: Role of glycogen synthase kinase 3 in TNFα-induced apoptosis in primary hepaticytes
  Details: Hepatocyte supply and optimizing culture conditions for studying signal transduction.

• Subject: Isolation of primary mouse hepatocytes.
  Details: The group isolates hepatocytes from mice with different genotypes.

Berlin - Mannheim

Nüssler - Dooley

• Subject: Investigation of TGF-ß signaling in human hepatocytes and Neo-Hep cells.
  Details: Establishing a collaboration, where we isolate monocytes from alcoholic patients and establish Neo-Hep cells from these in our lab for further investigations.

Holzhütter - Dooley

• Subject: Profiling and data analysis
  Details: Hepatocyte mRNA profiling and data analysis with respect to TGF.

Holzhütter/Gille - Dooley

• Subject: Metabolic network modeling
  Details: Sharing the microarray data and software (Metannogen) and metabolic networking modeling is generated.

Berlin - Jena

Zeilinger - Pfaff/Guthke

• Subject: Data-exchange
  Details: Mathematical data analysis and construction of dynamic models to describe and to predict the functional performance of human liver cell bioreactors.

Holzhütter - Guthke

• Subject: Metabolic modeling
  Details: Selected pre-processed data were provided for jointly further analysis and mechanistic modeling. The group of Holzhütter got these data for further modeling. This approach will allow to compare different strategies of modeling.

Holzhütter - Schuster

• Subject: Modeling of hepatocyte metabolism
  Details: Compilation of large-scale metabolic networks of human hepatocyte metabolism.

Holzhütter - Behre/Schuster

• Subject: Scientific exchange
  Details: Scientific exchange of enzymes and pathways of amino acid and central metabolism.

Berlin - Stuttgart

Holzhütter - Mauch

• Subject: Flux balance approach
  Details: Comparison of the experimentally obtained flux distributions with flux balance analysis results.

• Subject: Exchange of large-scale network models of the hepatic metabolism.

Holzhütter - Maier

• Subject: Scientific exchange
  Details: Scientific exchange of information on enzymes and pathways in hepatocytes with partners of the network detoxification.

• Subject: Kinetic model of cholesterol synthesis
  Details: The kinetic metabolic model developed in Stuttgart will serve as the main source of detail regarding cholesterol synthesis and homeostasis in our bile formation model.

Nüssler - Reuss/Zanger

• Subject: Supply of primary hepatocytes.
  Details: Primary hepatocytes for subsequent detoxification studies are provided by the group of Prof. Nüssler. In addition, the groups work on the continuous quality of the cell transport and the logistic.

Frey - Zanger

• Subject: Statin excretion
  Details: Preliminary scientific exchange about the excretion of metabolic end products of statin detoxification. As soon as our model is able to reliably predict primary (lipid) bile composition, intensive collaboration about the relation of lipid and statin excretion is intended.

Nüssler - Falkner-Tränkle

• Subject: Cultivation of human hepatocytes.
  Details: Planning of logistics, determination of quality parameters, optimization of culture conditions.

Nüssler - Burk

• Subject: Human hepatocytes.
  Details: The subproject SP2 of the platform cell biology is supplying the project with primary cultures of human hepatocytes for drug-induction experiments, as required in WP1 and WP8.

Bulik/Holzhütter - Reuss

• Subject: Coordination in similar research activities
  Details: This project bases on SP 2.1 of the Modeling platform. Development of sub-models for various metabolic pathways (e.g. fatty acid metabolism, citric acid cycle etc.) will be tightly coordinated with similar research activities in the detoxification network (M. Reuss, Stuttgart). Cooperation with experimental groups within HepatoSys will start as soon as we have developed a first satisfactory kinetic model of the hepatocyte intermediate metabolism.

Berlin - Erlangen

Holzhütter - Gasteiger

• Subject: Flux-balance approach
  Details: The specific features of the BIOPATH (biochemical pathways) data base developed in the group of Gasteiger and the experimental flux analysis (Group of Reuss) were edited together. Two meetings (Stuttgart, Erlangen 2005) were devoted to the problem of efficiently merging the BIOPATH pathway data base with the stochiometric hepatocyte model built up by the Holzhütter group, local installation of the BIOPATH data base.

Berlin - Heidelberg

Herzel - Klingmüller

• Subject: Mathmatical modeling of STAT3 signaling.
  Details: Establishment of a mathematical model capturing signaling initiation by receptor activation and spatial effects.

Herzel - Nickel

• Subject: Mathmatical Modeling
  Details: Analysis of microarray data, establishment of a mathematical model for Smad signalling primary hepatocytes.

Holzhütter - Golebiewski

• Subject: Data exchange
  Details: Data and Literature was provided from Berlin that is used to populate the SABIO-RK database. Reactions were defined for a kinetic model of the hepatocyte metabolism and SABIO-RK is now populated with kinetic data for these reactions. The Holzhütter group in Berlin will use these data to generate such a metabolic model.

Holzhütter - Kummer

• Subject: Exchange of information on kinetic properties
  Details: Exchange of information on kinetic properties of enzymes with partners of the SYCAMORE project (SP 3.4).

• Subject: Modeling the metabolism of hepatocytes
  Details: The whole platform modeling is involved in setting up a quantitative model of the most important parts of the metabolism of hepatocytes.

Reich - Kummer

• Subject: Deterministic, stochastic and hybrid modeling techniques.
  Details: Discussions on deterministic, stochastic and hybrid modeling techniques, evaluation of Copasi as a possible modeling tool of choice.

Reich - Höfer

• Subject: Mathematical modeling techniques.
  Details: Discussions on the efficient stochastic simulation of a Master equation and the transferability of equilibrium-state simulations to non-equilibrium conditions.

Herrmann - Höfer

• Subject: Mathematical modeling techniques.
  Details: Discussions on efficient strategies for fitting of deterministic and stochastic simulation results to experimental data.

Nüssler - Klingmüller/Bohl

• Subject: Supply of primary hepatocytes.
  Details: Primary hepatocytes for subsequent regeneration studies are provided by the group of Prof. Nüssler.

Bulik - Golebiewski

• Subject: Exchange of kinetic data with the SABIO-RK database
  Details: Our kinetic model benefits by the data gathered in the SABIO-RK project and our experience with the services provided enable us to give feedback for further improvments.

Berlin - Magdeburg

Holzhütter - Klamt

• Subject: CellNetAnalyzer package
  Details: Integration of the stoichiometric model with the CellNetAnalyzer software tool.

Chauhan/Herzel - Huard/Gilles

• Subject: Integrative model of the cell cycle
  Details: We aim to create an integrative model of the cell cycle using two different approaches: detailed cell cycle model (Huard/Gilles) and mesoscale model to reproduce experimental finding of 2/3 and 1/3 PH (Chauhan/Westermark/Legewie/Herzel). Both approaches profit from each other and will be combined in the future.

Hoppe/Holzhütter - Klamt

• Subject: Integration of relevant gene expression-based sub-networks in CellNetAnalyzer
  Details: The integration of the hepatocyte network and relevant gene expression-based sub-networks in CellNetAnalyzer (formerly FluxAnalyzer) allows comparative studies of structural properties, such as minimal cut sets and elementary modes, etc. with state-of-the-art topological and flux-balance methods (SP 1.3).

Bölling - Mirschel/Gilles

• Subject: Model visualization
  Details: Visualization of the stoichiometric model metabolism of the hepatocyte.

Hoppe/Holzhütter - Mirschel/Gilles

• Subject: Visualization of gene-expression based hepatocyte sub-networks in the context of the whole network
  Details: Sophisticated tools to visualize the results are being developed in the project of Mr. Mirschel (SP 3.3) specifically designed to meet the requirements of the hepatocyte network with respect to size, complexity and compartmentalisation. The objective of this cooperation is the visualization of sub-networks in the context of the whole network.

Hoppe/Holzhütter - Bannasch

• Subject: Modeling function-specific gene expression data for the hepatocyte network
  Details: The cooperation with SP 4.1., central data management, will be our main interface to obtain relevant and function-specific gene expression data within the HepatoSys consortium.

Berlin - Leipzig

Herzel - Gebhardt

• Subject: Wnt signaling
  Details: Collaboration on a wnt signaling model, beta-catenin related zonation and cell cycle dynamics.

• Subject: Circadian Rhythm
  Details: Collaboration on a model for circadian rhythm control in liver.

Zeilinger - Gebhardt

• Subject: Investigation of zonation processes in 3D bioreactor co-cultures of human hepatocytes and non-parenchymal cells
  Details: Characterization of enzymatic parameters of hepatocytes in the liver reactors of the group of Zeilinger; parts of the reactors were sent from Berlin to Leipzig where the analysis was performed; these data will help to determine the ratio of periportal and pericentral hepatocytes within the liver bioreactor, which determines its metabolic capacity.

von Weizsäcker - Gebhardt

• Subject: Periportal hepatocytes
  Details: Investigating of the phenotype of periportal hepatocytes.

Knobeloch - Gebhardt

• Subject: Supply of primary hepatocytes
  Details: Primary hepatocytes for subsequent cell biology studies are provided by the group of Knobeloch.

Holzhütter - Gebhardt/Zellmer

• Subject: Liver parameters
  Details: Scientific exchange of parameters of the liver in various physiological states.

Holzhütter - Gebhardt

• Subject: Amino acid metabolism model
  Details: The groups of Holzhütter and Schuster will use the amino acid metabolism model generated in Jena/Leipzig to verify larger models of hepatic metabolism.

Berlin - Bochum

Holzhütter - McCaskill

• Subject: Compartment differentiation through the vesicular transport of endocytosis
  Details: Extention of the Heinrich and Rapoport’s model to answer the question how are proteins localized to give compartment identities.

Marcus - Nüssler

• Subject: Supply of primary hepatocytes
  Details: Primary hepatocytes for subsequent proteome analysis are provided by the group of Prof. Nüssler.

Berlin - Tuebingen/Reutlingen

Affeld/Kertzscher - Angres

• Subject: Quantification of hepatocyte proliferation on MSA (Multiple Substrate Arrays) chips by automated image analysis
  Details: Proliferation rates and morphology of hepatocytes on a variety of different extracellular matrix proteins is being analysed on the microarrays. Images generated from hepatocyte cultures on microarray chips are sent to partners Affeld and Kertzscher. Partners are developing image analysis algorithms for automated quantification of hepatocyte morphology and proliferation.

• Subject: Cell imaging of hepatocytes
  Details: Development of a method for analyzing microscopy images of hepatocytes. The aim is the discrimination of the morphologic state of hepatocytes.

Holzhütter - Bonin

• Subject: Metabolic function and gene expression in the context of statin medication
  Details: We recieved expression profiles from SP 9, Development of transcriptional networks and their regulation in statin treated hepatocytes, of the Detoxification network. We analyzed the data, mapped it to HepatoNet and communicated about the results. Next, we estimate the functional subnetworks according to the profiles to investigate the pleiotrophic effect of statin medication.

• Subject: Profiling and data analysis
  Details: mRNA profiling and data analysis with respect to bHMG-CoA-reductase inhibitors.

Holzhütter - Zell

• Subject: Automatized large scale modeling of hepatocyte systems
  Details: Prof. Holzhütter and his group are the leading experts of quantitative kinetic modeling within the HepatoSys consortium. In a joint diploma thesis we aim at developing a modeling pipeline based on SBML allowing us to automatize the assignment of reliable kinetic rate laws to reaction networks. A further cooperation regarding an integrated modeling approach including both, the regulatory and the metabolomic level is planned.

Berlin - Regensburg

Nüssler - Weiß

• Subject: Transport logistics, isolation proceedure, quality control
  Details: Exchange of Logistics, SOP and adaptation of technology. Exchange of students and technicians.

Berlin - Dortmund

Affeld - Hengstler

• Subject: Development and testing of flow devices.
  Details: The aim is the development of a flow device for investigating cells under different environmental conditions (shear stress, temperature, pH-value, etc.).

• Subject: Technical support for experiments (microscopy).
  Details: The heat distribution inside the new incubator has been improved. The problem of condensation at the well-plate top cover which influenced the illumination of the cells was solved resulting in an improvement of the image processing.

• Subject: Cell imaging of time lapse videos.
  Details: A method was developed for analyzing the time lapse videos of cultured hepatocytes according to the specific demands of the group of Prof. Hengstler. Objects (cells, nuclei) and events (deaths, divisions etc.) were marked manually and analyzed automatically. Several videos were and will be analyzed.

von Weizsäcker - Hengstler

• Subject: SOPs
  Details: Refining and optimizing the existing SOPs, transfer of the isolation procedure.

• Subject: Technical support for experiments (microscopy).
  Details: The heat distribution inside the new incubator has been improved. The problem of condensation at the well-plate top cover which influenced the illumination of the cells was solved resulting in an improvement of the image processing.

Herzel - Hengstler

• Subject: hepatocyte proliferation
  Details: Development of experimental conditions and measurement techniques for hepatocyte proliferation.

Holzhütter - Maeke

• Subject: Extension of the Heinrich-Rapoport model
  Details: The collaboration aims to link up our theoretical tools (reactive DPD) on the elaborated models of endocytotic compartment differentiation via vesicular traffic with the chemical kinetic analysis.

Nüssler - Hengstler

• Subject: Supply of primary hepatocytes and sharing information and technics in both laboratories regarding the signal pathway.
  Details: With reference to the medical and pharmacological relevance of models generated with cultured hepatocytes it should be guaranteed that modeling performed in vitro is relevant to the in vivo situation of the intact liver. Therefore, we will stimulate the intact organ by injection of, for instance, HGF, IL6 or insulin into the portal vein. This procedure will allow comparing the dynamics of signaling in vivo and in vitro. Our Cooperation will compare the generated data with the human situation.

Zeilinger - Hengstler

• Subject: Validation of the metabolic activity of cultured mice and human hepatocytes
  Details: Characterisation of hepatocyte preparations with respect to heterogeneity. Influence of relative representation of subpopulations on performance in bioreactors.

Magdeburg - Freiburg

Gilles - Mohr

• Subject: Modeling of EGF-signaling pathways
  Details: Mutual visits and talks.

Gilles - Borner

• Subject: Modeling apoptosis
  Details: Mutual visits and talks.

Gilles - Timmer

• Subject: Mathematical analysis of generated data for the modeling tool ProMoT/DIVA
  Details: Transfer of the advanced parameter estimation methods based on the multiple-shooting approach developed in the Timmer group for implementation in the modeling tool.

Gilles - Bartolome Rodriguez

• Subject: Modeling of IR and IRS-1 phosphorylation
  Details: A minimalistic model is being developed to explain IR and IRS phosphorylation kinetics. Thereby, the identification of the minimally required elements that generate the observed bell shaped dose-response curves of IR- and IRS-phosphorylation after insulin stimulation is the main goal in this collaboration. An intense literature research resulted in a preliminary model with only a few unknown parameters. Using our experimental time courses, unknown parameters will be identified.

Gilles/Conzelmann - Timmer

• Subject: Creation of reduced insulin signaling models
  Details: Cooperation with M. Koschorreck of our group and the group of Prof. Timmer with the aim to create reduced models of insulin signaling also using some of our reduction techniques.

Bannasch - Timmer

• Subject: Data management
  Details: Contribution to the requirement specification for data management system for the competence network.

Bannasch - Kreutz

• Subject: Standardization of non-high throughput data, development of a relational database scheme for the storage of these data and realization of a pilot project until January 2009
  Details: It has turned out that the database for HepatoSys is not capable to store non-high-throughput data in a relational database format. Therefore, it is not possible to query such data nor to link them to other data produced in the network. In order to overcome this situation, it is necessary (a) to standardize these data, (b) to develop a relational database format in order to store such data and (c) to set up a corresponding relational database which allows for a user-friendly data storage, for querying the database and for retrieval of significant data. Step (a) has been performed primarily in cooperation of S. Bohl, C. Kreutz and D. Bannasch; step (b) was performed primarily by D. Bannasch alone and step (c) is being realized by S. Dietmann. A pilot version of the database will be available in January 2009.

Mirschel/Gilles - Heisner

• Subject: Visualization of the Infrastructure of HepatoSys
  Details: Data survey for and development and implementation of an interactive illustration of the different working groups of HepatoSys and their collaborations. Visualization is available at http://www.hepatosys.de/.

Koschorrek/Gilles - Timmer

• Subject: Mathematical modeling of pro- and antiapoptotic signaling
  Details: Periodic meetings were performed to discuss the progress. Application of reduced modeling techniques in cooperation with H. Conzelmann (SP 1).

Koschorrek/Gilles - Merfort

• Subject: Modeling of NF-kB
  Details: Periodic meetings were performed to discuss the progress.

Koschorrek - Bartolome Rodriguez

• Subject: Experimental data for insulin signaling
  Details: Periodic meetings were performed to discuss the progress.

Bannasch - Bartolome Rodriguez

• Subject: Development of a data base for immunoblotting data
  Details: Cooperation in the development of minimal requirements for the newly developed data base for immunoblotting data.

Samaga/Klamt - Rho/Timmer

• Subject: Modeling of HGF signaling
  Details: Exchange of results of Boolean and dynamic modeling of HGF signaling.

Magdeburg - Heidelberg

Mirschel/Gilles - Kummer

• Subject: Tool integration
  Details: Tight collaboration on tool integration which has strong impact on the software tools SYCAMORE and ProMoT.

Rempel/Gilles - Kummer

• Subject: Model merging
  Details: Tight collaboration on model merging which has strong impact on the software tools SYCAMORE and ProMoT.

Rempel/Gilles - Rojas

• Subject: Database assisted identification
  Details: SABIO-RK based annotations to improve identification of corresponding model elements.

Samaga/Klamt - D'Alessandro/Klingmüller

• Subject: Logical model of HGF signaling
  Details: Exchange of knowledge of the HGF signaling pathway in hepatocytes to build up a comprehensive logical model; use of model predictions for experimental design; comparison of model predictions and experimental data.

Huard/Gilles - Müller/Klingmüller

• Subject: Supply of experimental data from proliferating murine cells for modeling the cell cycle
  Details: Supply of experimental data from proliferating murine cells after stimulation by growth factors (EGF, HGF) for modeling the cell cycle.

Bannasch - Dietmann

• Subject: Standardization of non-high throughput data, development of a relational database scheme for the storage of these data and realization of a pilot project until January 2009
  Details: It has turned out that the database for HepatoSys is not capable to store non-high-throughput data in a relational database format. Therefore, it is not possible to query such data nor to link them to other data produced in the network. In order to overcome this situation, it is necessary (a) to standardize these data, (b) to develop a relational database format in order to store such data and (c) to set up a corresponding relational database which allows for a user-friendly data storage, for querying the database and for retrieval of significant data. Step (a) has been performed primarily in cooperation of S. Bohl, C. Kreutz and D. Bannasch; step (b) was performed primarily by D. Bannasch alone and step (c) is being realized by S. Dietmann. A pilot version of the database will be available in January 2009.

Bannasch - Bohl/Klingmüller

• Subject: Standardization of non-high throughput data, development of a relational database scheme for the storage of these data and realization of a pilot project until January 2009
  Details: It has turned out that the database for HepatoSys is not capable to store non-high-throughput data in a relational database format. Therefore, it is not possible to query such data nor to link them to other data produced in the network. In order to overcome this situation, it is necessary (a) to standardize these data, (b) to develop a relational database format in order to store such data and (c) to set up a corresponding relational database which allows for a user-friendly data storage, for querying the database and for retrieval of significant data. Step (a) has been performed primarily in cooperation of S. Bohl, C. Kreutz and D. Bannasch; step (b) was performed primarily by D. Bannasch alone and step (c) is being realized by S. Dietmann. A pilot version of the database will be available in January 2009.

Bannasch - Golebiewski

• Subject: Linking of the Sabio-RK database to Phylosopher and vice versa
  Details: Protein entries in Phylosopher have been linked directly to EC numbers and the corresponding enzymes in the Sabio-RK database of reaction kinetics and vice versa. In this way, it is possible on the one hand to navigate from an enzyme involved in a metabolic reaction which is stored in the Sabio-RK database to the summary page of the corresponding protein in Phylosopher. This page presents additional data concerning the protein and links to other database entrys of Phylosopher. On the other hand, it is possible to navigate from the protein summary page of an enzyme stored in Phylosopher both to the corresponding enzyme (work still in progress) and to the corresponding enzyme class in Sabio-RK.

Magdeburg - Stuttgart

Klamt - Reuss

• Subject: CellNetAnalyzer
  Details: The CellNetAnalyzer package has been provided for structural network studies (minimal cut sets).

Samaga/Klamt - Schlatter/Sawodny

• Subject: Integrated logical model of signaling pathways
  Details: ---

Magdeburg - Leipzig

Magdeburg - Bochum

Bannasch - Marcus

• Subject: Data management, software evaluation
  Details: Integration of proteomics data; improvement of Refiner MS software (Genedata).

Magdeburg - Jena

Samaga/Klamt - Schuster

• Subject: Structural analysis of signal transduction networks
  Details: Theoretical methods for structural network analysis; Logical modeling of insulin signaling pathway.

Samaga/Klamt - Guthke

• Subject: Interaction graphs; merging of dynamic models
  Details: i) Exchange of ideas for bridging the gap between knowledge-based and data-based network reconstruction methods by using interaction graphs ii) Merging of dynamic models inferred from transcriptome, metabolome and signal proteome time series data.

Magdeburg - Wurzburg

Gilles - Dandekar

• Subject: Mathematical modeling
  Details: Investigation and analysis of pro- and antiapoptotic pathways in hepatocytes.

Magdeburg - Munich

Bannasch - Genedata AG

• Subject: (1) Development of the model block for the database of HepatoSys by Genedata. The development took place in close collaboration with the central data management of HepatoSys (monitoring of the development process and testing). The current version of the model block (version 1.2) was released by Genedata in 11/2007.
  (2) Joint organization of user trainings for the members of HepatoSys.
  (3) Participation of two trainers of Genedata in the "Advanced user workshop" organised by the central data management in 05/2007.
  (4) Joint efforts to solve problems with the database.
  (5) Improvements of the database.
  Details: Until 05/2007, user support given for the HepatoSys members by Genedata's helpdesk, software updates and the correction of software bugs by Genedata was subject of a maintenance agreement between the MPI Magdeburg and Genedata. In 09/2007 a Professional Services Agreement between Genedata and the MPI Magdeburg (on behalf of HepatoSys) was concluded which terminates in 2010. It serves to finance user support given by Genedata's helpdesk, to allow for user trainings performed by Genedata (on demand), to provide consulting (on demand) and to realize minor software improvements or developments as well as bug removal from the Genedata software. Details of the cooperation:
  
  (1) Genedata has developed the model block of the database for HepatoSys until 10/2007. The model block has been connected tightly to Phylosopher which is a central part of the existing database. The development was based on the requirement specification (Pflichtenheft) for an integrated database for HepatoSys. The development process of the model block has been monitored by the central data management of HepatoSys. About 90% of the requirements have been successfully fulfilled.
  
  (2) According to the license contract with the MPI Magdeburg, Genedata has offered introductory trainings that aimed to explain the usage of the software to the HepatoSys members. These trainings have been organized in close cooperation of Genedata and the central data management for HepatoSys.
  
  (3) Two trainers of Genedata were invited to speak about important topics of the database for HepatoSys on the "Advanced user workshop" that was organised on the 7th of May 2008 at the MPI Magdeburg by the central data management. They presented information concerning the project management in Expressionist and concerning the state of the development of the model block, respectively.
  
  (4) Problems that occur during the usage of the database are solved as far as possible by the central data management of HepatoSys alone. For more severe problems, the helpdesk unit of Genedata is contacted for support.
  
  (5) Currently (12/2008), some improvements of the existing database (primarily concerning the model block) are being planned which are supposed to be performed by Genedata.

Heidelberg - Leipzig

Klingmüller - Gebhardt

• Subject: Studies on STAT-signalling pathway and interference with SnoN
  Details: Definition of target genes and proteins for TGF-ß that respond to SnoN feedback inhibition. Application of SnoN transgenic mice and their use for whole-liver studies.

Nickel - Gebhardt

• Subject: Pathology of SnoN knockin mice
  Details: Analysis of induction of apoptosis, establishment of proliferation assay.

Freiburg - Leipzig

Walz/Merfort - Gebhardt

• Subject: Studies on the NFkB-Signaling pathway

Merfort - Gebhardt

• Subject: Transfection of primary hepatocytes
  Details: Application of siRNA knock-down for studying NFkB signalling. Further aspects concern alterations of gene expression during the early phase of cultivation and possible strategies for their prevention.

• Subject: Primary hepatocytes
  Details: Transfection of primary hepatocytes.

• Subject: Dedifferentiation, cultural adaptation, proliferation of hepatocytes
  Details: In addition to the aspects mentioned in detail in the cooperation with Prof. Hengstler, there is a collaboration on the subject of efficient transient transfection of heopatocytes (AG Nitschke).

• Subject: Characterization of cultured mouse hepatocytes by gene array analysis
  Details: Affymetrix gene arrays of stimulated and non-stimulated hepatocytes were analyzed. Changes in gene expression during the course of cultivation was followed. Primary results indicate that metabolic genes are down-regulated and genes related to extracellular matrix are upregulated.

Timmer - Bader

• Subject: Epo-receptor
  Details: Working in common on the analysis.

Hecht - Gebhardt

• Subject: Modeling of Wnt/ß-catenin pathway in hepatocytes
  Details: The group of Hecht identified Wnt-factors, which activate the pathway, relevant cell cultures were established in Leipzig and the Wnt-factors were identified in Freiburg (Gebhardt et al. 2005), work will be extended to other LEF/Tcf target genes (e.g. axin), therefor the inter-network collaboration works now with respect to the characterization of a set of novel GSK3ß inhibitors (L4, L7, and L10), Prof. Gebhardt provided Dr. Hecht with samples of these chemicals which are applied to the cell culture systems, the group of Dr. Hecht analyzed whether these substances were capable of inducing a cytoplasmic pool of hypophosphorylated ß-catenin and of activating target gene expression. All three agents induced partial activation of Wnt/ß-catenin signaling, but compared to LiCl, SB216763 or Wnt3a proved to be less effective, the results of the experiments were returned to Prof. Gebhardt, the results are also important for the model calculations of the group of Holzhütter (Platform Modeling), the calculations will therefore be performed in Berlin and Freiburg.

Hecht - Drasdo

• Subject: Modeling of Wnt/ß-catenin and GH signalling
  Details: Modeling of interactions between Wnt/ß-catenin signaling and growth hormone signaling. Possible impact on hepatocyte heterogeneity (zonal expression of cytochromes P450 and glutamine synthetase).

Timmer - Gebhardt

• Subject: Modeling of induction of the glutamine synthetase after stimulation with LiCl
  Details: The wet lab experiments (induction of the glutamine synthetase after stimulation with LiCl) have been transferred to the group of Timmer for further modeling, this approach will allow to compare different strategies of modeling.

Jena - Leipzig

Pfaff/Guthke - Zellmer/Gebhardt

• Subject: Data exchange
  Details: Several hepatocyte transcriptome data sets were obtained from Leipzig and results of the respective data analysis as well as reconstructions of regulatory networks were returned to these groups.

• Subject: Modeling liver heterogenity
  Details: Analyzing of metabolic liver heterogeneity of periportal and pericentral hepatocytes using Affimetrix chip data in cooperation with the group of Dr. Guthke. The wet lab data were generated in Leipzig and the dry lab data were calculated in Jena. Modeling will be performed in Berlin. The data will be essential for modeling of liver heterogeneity.

• Subject: Modeling for the induction of the glutamine synthetase after stimulation with LiCl
  Details: Mathematical models for the induction of the glutamine synthetase after stimulation with LiCl were developed. The wet lab experiments were performed in Leipzig and the data analysis was done in Jena.

• Subject: Modeling of Gene Regulatory and Metabolic Networks in Hepatocytes
  Details: A dynamic model of the amino acid metabolism togehter with central elements of carbohydrates (glucose, lactose, pyruvate) as well as ammonia and urea was developed based on data from isolated mouse hepatocytes. The metabolism of 5 different isolated hepatocyte cultures were compared. Parameters will be identified, which are critical for the development of the culture conditons.

• Subject: Identification of a critical marker set of hepatocytes
  Details: Isolated hepatocytes were cultivated and changes of amino acids, glucose, pyruvate, lactate and urea in the culture medium were followed over the cultivation period. Principal component analysis was used to identify the urea metabolism as a characteristic parameter of the culture. Data were presented at the GASL (Zellmer et al. 2008).

• Subject: Characterization of cultured mouse hepatocytes by gene array analysis
  Details: Affymetrix gene arrays of stimulated and non-stimulated hepatocytes were analyzed. Changes in gene expression during the course of cultivation was followed. Primary results indicate that metabolic genes are down-regulated and genes related to extracellular matrix are upregulated.

Guthke - Bader

• Subject: Gene Expression Data Analysis
  Details: Gene expression analysis in different developmental states, e.g. embryonic to adult cells.

• Subject: Embryonic and adult hepatocytes
  Details: Influence of growth factors and matrix-cell interactions on embryonic and adult hepatocytes.

Leipzig - Bochum

Bader - McCaskill

• Subject: Application of intelligent (equipped with IT-potential) microfluidics for studying hepatocytes. "And" The experimental platform of Bader opens the possibility to investigate whole-cell behaviour in a controlled and physiologically relevant context
  Details: BioMIP will help develop confocal imaging options for model verification and present a potential analysis of smart microfluidics in hepatocyte research. "And" Complex processes such as transcytosis in an experimental setup with clearly defined overall polarity and temporal input/output-profiles will be made accessible for a quantitative study.

• Subject: Cultivation of hepatocytes
  Details: We already have tested the PDMS membranes (microfluidic structures) from the group of Prof. John McCaskill for the cultivation with primary hepatocytes. We also try to cultivate the hepatocyte in polymerizing collagen gel for the injection in the PDMS membrane channels. The hepatocyte cultivation on the PDMS membranes will be continued and adapted to the polarized model.

Leipzig - Stuttgart

Bader - Reuss

• Subject: Modeling of signaling and metabolism network
  Details: Providing of experimental data to verify the mathematical models.

Leipzig - Mannheim

Zellmer - Dooley

• Subject: SOPs
  Details: Establishing transfection protocols of primary cultured hepatocytes, the exchange of transgenic animals and reagents (e.g. Smad7 antibody for immunostainings) was organized.

• Subject: Expression of glutamine synthetase in hepatocytes transfected with ß-catenin
  Details: Cells were isolated, cultured, transfected and stained in Leipzig. Co-expression of glutamine synthetase and the GFP-ß-catenin construct was determined with high throughput analysis in the group of Emans. Techniques for transfection of primary hepatocytes and isolation of cells were transferred to this group.

Gebhardt - Dooley

• Subject: mouse model for TGF-ß1 overexpression

• Subject: siRNA knock-down technologies
  Details: In this cooperation siRNA knock-down strategies are explored, evaluated and transferred to automatic expression/detection systems. It is the goal to provide appropriate SOPs for siRNA knock-down studies within HepatoSys.

Leipzig - Tuebingen/Reutlingen

Gebhardt - Angres

• Subject: Development of protocols for hepatocyte proliferation
  Details: With Partner Gebhardt we are developing protocols for the optimization of ECM-dependent proliferation of mouse and human hepatocytes. Protocols include the timing of stimulation of hepatocytes with growth factors and BrdU-incorporation.

Gebhardt - Nordheim

• Subject: Immuno-histochemical examination of liver sections obtained from hepatocyte-specific Srf(-/-) mice
  Details: Breeding complete. Liver samples prepared. Transfer of specimen from Tuebingen to Leipzig arranged.

Leipzig - Ulm

Drasdo - Teutsch

• Subject: Liver anatomy
  Details: Prof. Teutsch performs manual reconstructions of liver lobules which can guide our automated procedures.

Leipzig - Dresden

Gebhardt - Zerial

• Subject: siRNA knock-down technologies
  Details: In this cooperation siRNA knock-down strategies are explored, evaluated and transferred to automatic expression/detection systems. It is the goal to provide appropriate SOPs for siRNA knock-down studies within HepatoSys.

Bader - Zerial

• Subject: Culturing and transfection of primary hepaotyctes
  Details: This involves the continues discussion for optimizing the culturing and transfection of the primary hepatocytes as well as the exchange of antibodies and reagents.

Leipzig - Regensburg

Gebhardt - Weiß

• Subject: Supply of primary hepatocytes
  Details: Primary hepatocytes for subsequent cell biology studies are provided by the group of PD Dr. Weiss and PD Dr. Thasler.

Leipzig - Dortmund

Drasdo - Hengstler

• Subject: Validation of our models
  Details: The group of Prof. Hengstler does the mice experiments to validate our models. The experiments include several partners.

Gebhardt - Hengstler

• Subject: Studies on STAT-signalling pathway and interference with SnoN
  Details: Definition of target genes and proteins for TGF-ß that respond to SnoN feedback inhibition. Application of SnoN transgenic mice and their use for whole-liver studies.

• Subject: Characterization of Hepatocytes
  Details: Cooperations between the groups of Rolf Gebhardt and Jan Hengstler were performed on different aspects within HepatoSys. - Both partners were responsible for the supply of hepatocytes within the network. This work was coordinated between both groups. - Primary hepatocytes as well as stem cell derived hepatocyte-like cells were characterized for specific enzymatic parameters (e.g. glutamine synthetase) and the change of these parameters at different culture conditions. - Data were exchanged, which enabled the group of Drasdo first modeling approaches of the regenerating liver lobulus and these results were discussed in order to improve the model. - Gene array analysis were performed using hepatocytes prepared by the group of Hengstler and the group of Gebhardt in a close cooperation with the group of Guthke (Jena) in order to evaluate differences between individual hepatocyte preparations, characteristics of hepatocyte sub-populations and differences between liver tissue as well as isolated cells.

• Subject: Characterization of cultured mouse hepatocytes by gene array analysis
  Details: Affymetrix gene arrays of stimulated and non-stimulated hepatocytes were analyzed. Changes in gene expression during the course of cultivation was followed. Primary results indicate that metabolic genes are down-regulated and genes related to extracellular matrix are upregulated.

Bader - Hengstler

• Subject: Cell immortalization
  Details: Establishment of a hepatic cell line by immortalization.

Bader - Maeke

• Subject: Biocompatibility tests
  Details: Exchange of microfluidic structures with the Bader group; testing of biocompatibility regarding hepatocytes and experiments for microfluidic integration of cellular model systems.

Leipzig - Duesseldorf

Gebhardt/Zellmer - Schliess

• Subject: Comparison of perfused mouse liver and mouse hepatocyte culture
  Details: Gene expression profiling and signal transduction analysis in cultured mouse hepatocytes and perfused mouse liver, analysis of zonated ammonia detoxication in perfused mouse liver.

Gebhardt - Schliess

• Subject: Sugar grant on integrating regeneration and detoxification into a dynamic model
  Details: A model of the nitrogen metabolism of the rat liver was adopted to the mouse liver. Perfusion data were exchanged and images were taken in order to integrate the visualization of a CCl4 intoxication on the glutamine synthetase activity into the model of the regenerating liver. Partner are Schliess, Häussinger, Zellmer, Gebhardt, Brulport, Hengstler, Höhme, Drasdo, Pfaff, Büntemeyer.

Jena - Dortmund

Guthke - Hengstler

• Subject: SOPs
  Details: Characterisation of hepatocyte preparations with respect to heterogeneity, influence of relative representation of subpopulations on performance in bioreactors.

• Subject: Regulatory networks
  Details: Reconstruction of regulatory networks responsible for hepatocyte differentiation.

• Subject: Modeling
  Details: Modeling of the Wnt/ß-Catenin pathway.

• Subject: Exploratory gene expression data mining
  Details: Similarities in features of the gene expression profiles during standard cultivation of hepatocytes in different laboratories were investigated by Principal Component Analysis and visualized in biplots.

Guthke/Schmitt-Heck - Hengstler

• Subject: Gene array analysis
  Details: The Guthke group has done all gene array data analyses for the group of Prof. Hengstler.

Jena - Tuebingen

Guthke - Zell

• Subject: Comparison of alternative modeling and inference methods for gene regulatory networks
  Details: The group of Dr. Guthke developed the network inference approach NetGenerator (Töpfer2007) which is mainly based on linear models. The subject of our cooperation is to evaluate the capabilities and applicability of our non-linear methods compared to the NetGenerator in a systematic study.

Jena - Duesseldorf

Pfaff - Schliess

• Subject: Liver regeneration and nitrogen metabolism
  Details: Modeling of mouse liver ammonia detoxication based on experimental data generated in Duesseldorf.

Freiburg - Jena

Timmer - Guthke

• Subject: Modeling
  Details: Selected pre-processed data were provided for jointly further analysis and mechanistic modeling. Development of mathematical models for the induction of the glutamine synthetase after stimulation with LiCl together with Prof. Gebhardt, Leipzig. The wet lab experiments were performed in Leipzig and the data analysis was done in Jena. The group of Timmer got these data for further modeling. This approach will allow to compare different strategies of modeling.

Merfort - Schmidt-Heck/Guthke

• Subject: Gene-expression data analysis and network reconstruction
  Details: Data analysis of the microarrays described in detail in the cooperation with Prof. Hengstler/Gebhard.

Borner - Schuster

• Subject: Regulatory and metabolic networks
  Details: Starting from metabolic modeling algorithms we have a long term scientific collaboration regarding all aspects of cellular networks, which profits in particular from the Hepatosys network.

Dresden - Heidelberg

Deutsch - Höfer

• Subject: Data exchange
  Details: Investigations on interrelation of endocytosis and signaling pathways.

Deutsch/Brusch - Klingmüller

• Subject: Modeling of TGF-ß
  Details: Modeling of TGF-ß internalization trafficking and signaling in primary hepatocytes.

Brusch - Höfer

Brusch - Wade/Kummer

• Subject: Protein structural models
  Details: Estimating parameters for mathematical models being developed at TU Dresden to interpret experimental data from MPI Dresden on the Rab5 machinery.

Deutsch - Kummer

• Subject: EndoSys
  Details: EndoSys.

Zerial - Kummer

• Subject: EndoSys
  Details: EndoSys.

Zerial - Klingmüller

• Subject: Contruct of endosome biogenesis and transport
  Details: Intensify interaction with other network modeling groups to facilitate and construct the reconstitution of a protein and lipid network of components acting in endosome biogenesis and transport.

Habermann - Wade

• Subject: Phylogenetic analysis (PYPer), functional prediction of proteins (ProFAT), domain prediction (HMMerThread database), structure prediction of endocytic proteins for comparative modeling and PIPSA analysis
  Details: Input and feedback for structure- and sequence- based phylogentic analysis of protein families, functional prediction and structure-based, functional analysis of proteins.

Dresden - Freiburg

Deutsch - Timmer

• Subject: Contruct of endosome biogenesis and transport
  Details: Intensify interaction with other network modeling groups to facilitate and construct the reconstitution of a protein and lipid network of components acting in endosome biogenesis and transport.

Dresden - Dortmund

Zerial - Hengstler

• Subject: Cellbiological analysis
  Details: Intensify interaction with other network modeling groups to facilitate and construct the reconstitution of a protein and lipid network of components acting in endosome biogenesis and transport.

Zerial - Maeke

• Subject: Detection
  Details: Enhancement of compatibility with MPI-experimental setup via installation of a DPSS laser (561 nm). Combination of intelligent microfluidics with multicolor detection.

• Subject: Pathway verification
  Details: Verification of pathway for Rab5 domain formation leading to budding of transport vesicle.

Dresden - Bochum

Deutsch - McCaskill

• Subject: Spatio-temporal whole-cell model
  Details: Incorporation of regulatory mechanisms of Rab GTPases into biophysical model of membrane dynamics by means of dissipative container dynamics.

Habermann - McCaskill

• Subject: Bioinformatics Input for the modeling of vesicle fusion/fission
  Details: Input of detailed molecular mechanisms and functional prediction of proteins involved in fusion/fission of vesicles in transport.

Brusch - McCaskill

• Subject: Model exchange, data exchange
  Details: Whole cell model of vesicular transport through integration of processes at multiple scales.

Zerial - McCaskill

• Subject: Transport processes of cellular compartments - association of simulation and image analysis
  Details: Investigations of the process of tubulation-driven sorting, where different alternative scenarios are proposed and explored by simulation. These alternatives can be ascertained in experiment by the different character of their kinetics calculated from simulations.

Dresden - Mannheim

Zerial - Dooley

• Subject: Endocytosis and signal transduction
  Details: Endocytosis and TGF-ß1 mediated signal transduction.

• Subject: Culturing and transfection of primary hepaotyctes
  Details: This involves the continues discussion for optimizing the culturing and transfection of the primary hepatocytes as well as the exchange of antibodies and reagents.

Deutsch/Brusch - Dooley

• Subject: TGF-ß signalling
  Details: Spatial-temporal pattern formation in TGF-beta signaling. Modeling of TGF-ß internalization trafficking and signaling in primary hepatocytes. Investigation of the role of internalization routes and receptor trafficking on TGF-ß signalling.

Habermann - Dooley

• Subject: Assistance in the analysis of expression data
  Details: assistance is given for the bioinformatics analysis of expression data.

Hamburg - Dortmund

Herrenknecht - Hengstler

• Subject: Supply with cultured mouse hepatocytes
  Details: Provision of primary hepatocytes is concerned, particularly with regards to establish conditions for preparation and shipment of frozen hepatocytes for this group.

Dortmund - Stuttgart

Hengstler - Zanger

• Subject: Hepatocytes, SOPs
  Details: Mutual exchange of protocols and know-how in hepatocyte culture; measurement of drug metabolism in various cell lines.

Hengstler - Mauch

• Subject: Hepatocytes
  Details: Receipt of primary hepatocytes.

Mannheim - Stuttgart

Dooley - Lange

• Subject: TGF-ß Pathway
  Details: For generating TGF-ß dependent target gene expression profiles in hepatocytes, we attended a meeting of the gene expression profiling consortium in Stuttgart and now have contact to the groups of Lange and Dippon (Stuttgart) for seeking a collaboration.

Stuttgart - Munich

Zanger - Nüssler

• Subject: Liver samples, human hepatocytes
  Details: Mutual exchange of protocols and know-how in hepatocyte culture; measurement of drug metabolism and inducibility in primary hepatocytes as a long-term quality assessment.

Stuttgart - Wurzburg

Sawodny - Dandekar

• Subject: Mathematical modeling
  Details: Investigation and analysis of pro- and antiapoptotic pathways in hepatocytes, efforts for integrated model.

Stuttgart - Freiburg

Witt - Timmer

• Subject: Mathematical modeling of apoptosis
  Details: Periodic meetings were performed to discuss the progress.

Witt - Merfort

• Subject: Mathematical modeling of NF-kB signaling
  Details: Several meetings to discuss the progress.

Witt - Borner

• Subject: Mathematical modeling of apoptosis
  Details: Periodic meetings were performed to discuss the progress.

Sawodny - Merfort

• Subject: Modeling of NF-kappaB signaling from Receptor to target gene expression
  Details: Our collaboration aims at modeling the TNF-alpha induced apoptotic signaling pathway in hepatocytes. Moreover, we work together in the setup of a signaling model of TNF-alpha and IL17 pathways.

Sawodny/Sauter/Schlatter - Borner

• Subject: Modeling apoptosis
  Details: Modeling FasL-induced apoptosis signaling.

Stuttgart - Regensburg

Burk - Weiß

• Subject: Xenobiotica metabolism in primary human hepatocytes
  Details: Primary hepatocytes for subsequent xenobiotica studies are provided by the group of PD Dr. T.S. Weiss and PD Dr. W.E.Thasler.

Reuss/Zanger - Weiß

• Subject: Supply of primary hepatocytes
  Details: Primary hepatocytes for subsequent detoxification studies are provided by the group of PD Dr. T.S. Weiss and PD Dr. W.E.Thasler. In addition, the groups work on the continuous quality of the cell transport and the logistic.

Falkner-Tränkle - Weiß

• Subject: Cultivation of human hepatocytes
  Details: Planning of logistics, determination of quality parameters, optimization of culture conditions.

Stuttgart - Tuebingen

Reuss - Bonin

• Subject: Data analysis and simulation
  Details: Data analysis and simulation.

Zanger - Bonin

• Subject: Microarray analysis of liver samples
  Details: Numerous microarray analyses of IKP liver samples were carried out by the microarray facility Tübingen which also offers support for data analysis.

Burk - Bonin

• Subject: Genome-wide identification of PXR binding sites
  Details: SP9 performs a genome-wide analysis of PXR binding sites in chromatin dependent on drug treatment, by ChIP on CHIP experiments. Newly identified PXR binding sites will be analyzed in SP4 for the kinetics of PXR-DNA interaction.

Falkner-Tränkle - Bonin

• Subject: Analysis of the transcriptome of hepatocytes
  Details: Induction experiments were carried out in the central cell biology laboratory and cells subsequently worked off for RNA isolation.

Reichart - Zell

• Subject: Analysis of rifampicin microarray analysis
  Details: We are in close contact with Thomas Reichart concerning the analysis of the rifampicin microarray data-set.

Zanger - Zell

• Subject: Microarray analysis of liver samples
  Details: RNA-profiling data of IKP liver samples are being evaluated using novel mathematical approaches. Regular meetings are being held to ensure progress.

Reuss - Schröder

• Subject: Inference of gene regulatory networks
  Details: Due to opposed approaches in reconstructing gene regulatory networks we are in contact with SP5 at regular intervals to compare and discuss new methods and findings.

Zanger - Schröder

• Subject: Application of data mining and machine learning algorithms to IKP liver tissue microarray data
  Details: Within this cooperation we investigate the capabilities of machine learning techiques to analyze static microarray data labeled with large amounts of additional patients information. The aim of this approach is to extract hidden relationships among expression data. Especially, the regulatory influences of key regulators of detoxification (nuclear receptors) are to be discovered.

Mauch - Zell

• Subject: Parameter estimation
  Details: Utilization of the global parameter estimation framework JavaEva.

Mauch - Schröder

• Subject: Parameter optimzation of large-scale metabolic networks
  Details: Main subject of SP7 is the modeling of hepatocyte metabolism. For parameter optimization our framework JAvaEva is used which provides different evolutionary optimization strategies. We assist in benchmarking various optimizaton algorithms regarding the metabolic network constructed in SP7.

Heidelberg - Stuttgart

Kummer - Reuss

• Subject: Evaluation of modeling simulation tools
  Details: Providing models for testing model reduction methods.

Kummer - Schmid/Pleiss

• Subject: Detoxification in hepatocytes
  Details: Modeling and simulation of cytochrome P450s.

Kummer - Mauch

• Subject: Modeling of the central carbon metabolism of primary human hepatocytes
  Details: Model is made available to the group of Kummer, model will be used for validation of simulation tools developed at EML Research gGmbH.

• Subject: Model database
  Details: The reaction database SABIO-RK is accessed for set-up of the dynamic network models.

Wade - Pleiss

• Subject: Modeling of the protein interactions
  Details: We collaborated with the platform Bioinfomatics/Modeling. During several project meetings, software (PIPSA) and unpublished data was exchanged between the groups.

Erlangen - Stuttgart

Gasteiger - Schmid/Pleiss

• Subject: Cytochrome P450 Modeling
  Details: Prediction of the regioselectivity of the phase I metabolism by cytochrome P450.

• Subject: Calculation of biochemical properties of small organic molecules
  Details: We had several project meetings with project A1 (AG Gasteiger) for the simulation of small organic molecules and the calculation of their reactivities and sterical hindrance. AG Gasteiger provided us with their tool PETRA for estimation of chemical reactivities of small organic molecules. In addition, project A1 developed new 3D-descriptors in order to improve the predictions based on ligand-based modeling using our 3D models of the enzymes.

Gasteiger - Mauch

• Subject: Phase I Drug Metabolism
  Details: The databases on the endogenous and xenobiotic metabolism (BIOPATH resp. XENIA) developed in the group of Prof. Gasteiger have been linked to the INSILICO Biotechnology modeling software in order to automatically generate transition matrices.

Gasteiger - Zanger

• Subject: Model Validation
  Details: Experimental data from IKP is used to validate the selectivity models developed in the CCC.

Bochum - Stuttgart

Marcus - Schmid/Lange

• Subject: Comparative transcriptome and proteome analysis
  Details: Experimental data from the transcriptome and proteome analyses are compared and combined. Transcriptome data are used for targeted proteome analysis.

Marcus - Schmid/Reichart

• Subject: SP4, Microarray analysis
  Details: Our data from global differential analysis of the human hepatocyte (phospho)proteom monitoring effects caused by dedifferentiation and xenobiotics detoxification processes were compared with transcriptomic data produced by T. Reichart.

Marcus - Zanger

• Subject: SP3, Liver tissue bank, Pharmacogenetics/polymorphism
  Details: Establishment, evaluation and validation of the quantitative analysis of CYP was done in microsomes of liver tissue bank provided by U. Zanger. The amount of CYP2D6 in microsomes of human liver was compared to western-blotting and kinetic measurements from the group of U. Zanger.

Marcus - Zanger/Eichelbaum

• Subject: CYP450 induction/dedifferentiation; AQUA
  Details: Results from the IKP concerning CYP450 induction and dedifferentiation processes in primary hepatocytes provide the basis for the differential proteome study (selection of time points etc.).

• Subject: CYP450 induction/dedifferentiation; AQUA
  Details: The MPC provides new established methods for an absolute quantification of relevant proteins involved in phase I and phase II metabolism.

Marcus - Reuss

• Subject: Model validation
  Details: Modeling data from the IBTV is confirmed by experimental proteome data at the MPC to validate the models. Additionally absolute quantification (AQUA) of relevant (membrane) proteins involved in phase I and phase II metabolism is used for model validation.

• Subject: Sample supply
  Details: Primary hepatocytes are centrally prepared at the IBTV for subsequent proteome analysis.

Marcus - Bucher/Reuss

• Subject: Dymamic modeling of drug metabolism
  Details: Quantification of CYP3A4, UGT1A1 and CYP2D6 has been carried out for the subproject of J. Bucher / Prof. Reuss (SP5). The experiments have been planned by J. Bucher, analysis using quantitative near infrared detection based western blotting and mass spectrometry have been carried out in our laboratory. The results of this quantification have been directly submitted to the Reuss group.

Marcus - Pleiss

• Subject: Development of AQUA technique
  Details: The cytochrome P450 database established by the group of Pleiss provides the basis fort he selection of suitable AQUA peptides.

Marcus - Falkner-Tränkle

• Subject: Characterization of membrane proteins and cytosolic proteins
  Details: For membrane proteins the focus lies on preparation and analysis of transport proteins and plasma membrane. Concerning cytosolic proteins the change of proteom caused by induction is of greatest interest. All experiments are done in the central cell biology laboratory at the IBVT (Stuttgart).

Marcus - Burk

• Subject: Protein quantification
  Details: SP8 will establish methods to quantify PXR and CAR protein levels by mass spectrometry and will perform the measurements.

Marcus - Vacun

• Subject: Z2, Produced standard operation procedures
  Details: In cooperation with the cell culture laboratory in Stuttgart, we optimized cell workup procedures that insure efficient interfacing between the cell culture laboratories and our group. The protocol that has been uploaded by G. Vacun enables all network members to ship their samples to us without risk of damaging the cell material.

Freiburg - Heidelberg

Timmer - Kummer

• Subject: Providing models for testing model reduction methods.

Timmer - Höfer

• Subject: Modeling of growth factor signaling through Jak/Stat pathways relevant in liver development and regeneration
  Details: Based on recent experimental data, it is planned to adapt the model of the interferon/Stat1 network to the IL 6/Stat3 pathway both of which exhibit similarly complex molecular mechanisms of nuclear transport of the Stat transcription factors.

Rho/Timmer - D'Alessandro

• Subject: Mathematical modeling
  Details: Generation of the mathematical model and model analysis.

Timmer - Keppler

• Subject: Modeling of vectorial transport of two different substrates by recombinant uptake (OATP1B3) and efflux (MRP2) transporters of human hepatocytes
  Details: Stably transfected in MDCKII cells, the model can simultaneously describe the different substrates for untransfected, single and double transfected cells, it shows that endogenous transporters, intracellular buffers, and paracellular transport play an additional, although minor role in this process, the kinetics of transport by uptake and efflux transporters have been successfully described by mathematical modeling.

Timmer - Klingmüller

• Subject: Modeling of TGF-ß pathway
  Details: Providing models for testing model reduction methods.

• Subject: Epo-receptor
  Details: Working in common on an analysis.

• Subject: Modeling of TGF-ß internalization trafficking and signaling in primary hepatocytes.

• Subject: Several hepatocyte signaling pathways (STAT, MAPK, Wnt/ß-catenin)
  Details: Experimental planning, model building and evaluation in close collaboration.

• Subject: Mathmatical modeling of STAT3 signaling
  Details: Establishment of a mathematical model capturing signaling initiation by receptor activation and spatial effects.

Bartolome Rodriguez - Bohl

• Subject: Technical collaboration. Optimization of Immunoblotting procedures
  Details: This involves the details of the generation of quantitative Western blot data for example by using random samples to reduce systematic errors caused by the protein transfer from gel to membrane. The introduction of "normalizers" allowed a further reduction of systematic errors caused by pippeting error and measurement errors in protein quantification.

Merfort - Klingmüller

• Subject: SOP for quantitative real-time PCR
  Details: Identification of Housekeeping genes in Hepatocytes for quantitative real-time PCR analysis.

Freiburg - Dortmund

Timmer - Hengstler

• Subject: SOPs
  Details: Development of the experimental design for fixing the standard operating procedures for primary mouse hepatocytes.

von Weizsäcker - Hengstler

• Subject: SOPs
  Details: Refining and optimizing the existing SOPs, transfer of the isolation procedure.

Merfort - Hengstler

• Subject: SOPs
  Details: Refining and optimizing the existing SOPs, quality control of cultured hepatocytes.

• Subject: Dedifferentiation, cultural adaptation, proliferation of hepatocytes
  Details: Our cooperation aims to characterize the changes of primary hepatocytes when transfered from liver into culture according to SOP. We are interested to learn which characteristic changes are involved and what influence results on time resolved gene expression. Further we want to analyze, when dedifferentiation processes start and what are the hallmarks of this process on gene expression level. To this aim, we co-analyzed gene expression profiles of hepatocytes after different times in culture and found in two independent microarray-experiments that murine hepatocytes show the most prominent changes in gene expression within the first 24h of cultivation. Genes related to metabolism are down-regulated and genes related to proliferation, cell-cell and cell-matrix contacts are up-regulated. Another subject of collaboration is targeted towards efficient induction of proliferation in SOP cultured hepatocytes.

Freiburg - Mannheim

Timmer - Dooley

• Subject: Modeling of TGF-ß internalization trafficking and signaling in primary hepatocytes
  Details: Establishing of equations for a mathematical model of endocytosis in TGF-beta signalling, defining the steps of the TGF-ß signaling pathway, that need to be quantitatively determined. Jointly analyzing of the data.

Freiburg - Erlangen

Merfort - Terfloth

• Subject: Sesquiterpene Lactones Inhibitory Activity on Serotonine Release and on NF-kB
  Details: chemoinformatics modeling of 54 structurally different sesquiterpene lactones; comparison of models for inhibitory acitivity on serotonine release and on NF-kB to identify similarities and differences in the structural requirements for both activities.

Freiburg - Tuebingen

Timmer - Nordheim

• Subject: Help understanding the data requirements necessary to enable systems biological modeling
  Details: Discussions, no experimental work yet.

Hecht - Dräger/Schröder/Zell

• Subject: Methods of gene regulatory network inference
  Details: Assessment of different methods of gene regulatory network inference (probabilistic network, differential equation based model, indirect and direct structure optimization methods).

• Subject: Comparison of modeling approaches based on non-linear differential equation systems for reverse engineering of gene regulatory networks
  Details: Collaboration with members from the HepatoSys detoxification platform resulted in a poster at the SBMC. Further work aims at the publication of these results especially focussing on multi-objective network inference.

Freiburg - Wurzburg

Timmer - Dandekar

• Subject: Mathematical modeling of signalling cascades
  Details: Partner (theoretical modeling) in project C1, long term cooperation partner on all general questions on systems biology and expert on integrated models as well as time series analysis.

Freiburg - Duesseldorf

Merfort - Schliess

• Subject: Gene expression profiling
  Details: Modulation of IL6-induced gene expression profiles in cultured mouse hepatocytes by IL1beta and cellular dehydration.

Merfort - Bode

• Subject: Modeling of the NF-kB dependent influence of IL-1beta on gene expression and proliferation in Hepatocytes
  Details: Regeneration of hepatocytes is a complex growth process being regulated by a coordinated network of different signal transduction pathways. Whereas TNF-a and other cytokines, such as IL-6 are important for the initiation and propagation of liver regeneration, IL-1beta is a potent inhibitor of liver regeneration and hepatocyte proliferation. NF-kappaB activation represents a key event in IL-1beta signalling which does not only influence NF-kappaB target genes but also antagonizes signalling via the Jak/STAT cascade important for the signal-transduction of cytokines and growth factors such as IL-6. We therefore attempt to model the time and concentration dependent activation of NF-kappaB and its target genes in response to IL-1beta and its impact on IL-6 induced target genes and hepatocyte proliferation.

Heidelberg - Mannheim

Klingmüller - Dooley

• Subject: SOPs
  Details: Generation of SOPs for hepatocyte isolation, culture and transport, which had to be specifically modified in dependence of the investigation (e.g. signal transduction, imaging, adenovirus infection).

• Subject: TGF-ß signaling pathway
  Details: Intrinsic overlap with activities regarding the chronic damage and the regeneration of the liver; both groups had and will have frequent meetings to discuss strategies, share data and reagents and adapt SOPs for various investigations, e.g., adenoviral infection, phosphoprotein analysis, reportergene analysis, mRNA expression analysis of TGF-ß target genes in hepatocytes and so on; in future on jointly goal is the generation of TGF-ß dependent target gene expression profiles in hepatocytes; some of the array data will be used by the group of Klingmüller for quantitative evaluation.

Kummer - Dooley

• Subject: Modeling
  Details: Modeling TGFbeta signalling, EndoSys.

Nickel - Dooley

• Subject: Determination of fibrosis induction
  Details: CTGF staining.

Heidelberg - Duesseldorf

Klingmüller - Bode

• Subject: Modeling the inhibitory effects of IL-1 on IL-6 signaling in Hepatocytes
  Details: IL-6 signaling via gp130 is important for liver regeneration. IL-1 is thought to be an important inhibitor of liver regeneration and an antagonist of IL-6-mediated STAT3 activation. This effect of IL-1 is time dependently mediated by activation of p38. In cooperation with the group of Jen Timmer (Freiburg) we therefore attempt to model the time and concentration dependent activation of the p38/MK2 pathway by IL-1 beta and its influence on gp130 dependent STAT3 signaling.

Bohl - Bode

• Subject: Establishment of SOPs
  Details: Establishment of SOPs for ChIP and experimental conditions for quantitative immunoblotting for TNF-alpha induced STAT3 activation.

Kummer - Dooley

• Subject: Modeling
  Details: Modeling signal transduction pathways.

Heidelberg - Dortmund

Bohl/Klingmüller - Hengstler

• Subject: Analysis of signaling pathways
  Details: Special SOPs for the preparation, cultivation and starvation of primary murine hepatocytes have been developed.

Nickel - Hengstler

• Subject: Pathology of SnoN knockin mice
  Details: CCl4 treatment to induce hepatocyte regeneration in SnoN knockin mice, injection of TGFbeta.

D'Alessandro - Hengstler

• Subject: Generation of biochemical data and hepatocyte proliferation
  Details: Generation of biochemical data on MAPK pathway. Development of experimental conditions and measurement techniques for hepatocyte proliferation.

Heidelberg - Tuebingen

Schütz - Nordheim

• Subject: Liver-specific inactivation of SRF
  Details: Liver-specific inactivation of SRF.

Klingmüller - Nordheim

• Subject: Function of STAT5 in hepatocytes
  Details: To aid the modeling of cellular signalling mechanisms (STAT signalling, GR signalling, MAPK signalling), we compare the components and strategies of these three signalling pathways. This is currently being done at the functional and qualitative levels and is soon to be complemented by kinetic comparisons.

Golebiewski - Dräger/Zell

• Subject: Kinetic rate equations, SBML to PDF
  Details: We contributed with our expertise to the development of SBML2LaTeX, a tool that converts SBML to human readable Pdf. We plan to integrate this tool in our user interface as soon as it becomes available. Another field of collaboration is the connexion between SABIO-RK and SBMLsqueezer, a tool that suggests kinetic rate equations for reactions.

Heidelberg - Martinsried

Klingmüller - Mann

• Subject: SILAC-labeled liver cell line as internal control to quantify protein changes in primary hepatocytes
  Details: We cooperated with Prof. Klingmueller’s lab to establish the "spike-in" strategy, which employs SILAC-labeled cell line as internal control to quantify the protein changes in primary hepatocytes.

Klingmüller - Halder

• Subject: Quantification of proteins of interest in the TGFß and IL-6 signal transduction cascade
  Details: Primary hepatocyte cell lysates were delivered IPs were delivered recombinant proteins were delivered Quantification results gained by our and their method were compared.

Klingmüller - Pan

• Subject: Quantitative proteomics and phosphoproteomics to study signaling events in mouse primary hepatocytes related to liver regeneration
  Details: For quantitative proteomic study, our first aim is set up a SILAC labled mouse liver cell line (e.g. Heap1-6) as an internal standard for studying primary hepatocyts. Next, we will use this approach to study signaling pathways involved in liver regeneration.

D'Alessandro - Zanivan/Mann

• Subject: Proteomic analysis
  Details: Full proteome and phosphoproteome analysis of HGF signalling in the primary hepatocytes cultured at different cell confluencies.

Dortmund - Mannheim

Hengstler - Dooley

• Subject: SOPs establishing/optimization and material transfer
  Details: We got rat tail collagen type I from J. Hengstler lab. SOPs for hepatocyte isolation, culture and transport, which had to be specifically modified in dependence of the investigation (e.g. signal transduction, imaging, adenovirus infection), were established. An animal model to monitor EMT of hepatocytes during fibrogenesis was generated. Discussing differences in the behaviour of hepatocytes in dependency of the culture system. Common publication and one in preparation.

Regensburg - Mannheim

Weiß - Dooley

• Subject: Investigation of TGF-ß signaling in human hepatocytes
  Details: Primary hepatocytes for subsequent TGF-ß signaling studies are provided by the group of PD Dr. T.S. Weiss and PD Dr. W.E.Thasler.

Tuebingen - Bochum

Bonin - Marcus

• Subject: SP9, comparative proteome/transcriptome analysis
  Details: Transcriptome analysis of selected human hepatocyte samples will provide candidates for targted qualitative as well as quantitative protein analysis of the respective candidates. The analyses will be done using exactly the same samples.

Tuebingen - Erlangen

Zell - Gasteiger/Terfloth

• Subject: Classification of CYP isoenzyme metabolization
  Details: The group of Prof. Gasteiger investigated the performance of different machine learning methods to predict metabolizing enzymes (CYP1A2, CYP3A4, CYP2C9) based on molecular descriptors (Terfloth2007). We are currently investigating alternative classification methods based on geometrical properties of the molecules which have been developed in our group (Fröhlich2005).

Munich - Dortmund

Athelogou/Definiens - Maeke

• Subject: Collaboration between simulating vesicles with mprDPD and recognizing the vesicle-processes with the image-processing software of Definiens
  Details: Meetings on how to improve the image-analysis-software and exchange of simulation data and analyzed image-data. Data-interfaces had been defined.

Athelogou/Definiens - Tangen

• Subject: Simulating vesicles
  Details: Collaboration between simulating vesicles with mprDPD and recognizing the vesicle-processes with the image-processing software of Definiens AG.

Duesseldorf - Dortmund

Häussinger/Schliess/Bode - Hengstler

• Subject: Comparison of perfused mouse liver and mouse hepatocyte culture
  Details: This group has established a technique of isolated perfused mouse livers. This technique has been used by our group.

Tuebingen/Reutlingen - Dortmund

Nordheim - Hengstler

• Subject: CCl4 treatment and phenotypic analysis of hepatocyte-specific Srf(-/-) mice
  Details: Breeding complete, animals about to be transferred from Tübingen to Dortmund.

• Subject: Teaching animal experimentation, specifically partial hepatectomy
  Details: Student went to host laboratory to learn hepatectomy.

• Subject: Partial hepatectomy on mice with gene knock-out in components of the MAPK signalling pathway
  Details: Cooperation activated by detailed experimental planning. Currently preparation for transfer of mice to Dortmund.

Angres - Hengstler

• Subject: Monitoring hepatocyte behaviour on ECM (Extracellular Matrix)microarray chips
  Details: Migratory behaviour is being monitored on microspots of the MSA (Multiple Substrate Array) by time lapse videomicroscopy. Effects of different compositions of extracellular matrix proteins on cell spreading and cell motility will be evaluated.

• Subject: Hepatocyte proliferation
  Details: The Angres group has established matrix chips where high numbers of different well-defined extracellular matrices have been spotted. This is used to study the influence of several matrices on proliferation events.

Regensburg - Dortmund

Weiß - Hengstler

• Subject: Supply of primary hepatocytes and sharing information and technics in both laboratories
  Details: With reference to the medical and pharmacological relevance of models generated with cultured hepatocytes it should be guaranteed that modeling performed in vitro is relevant to the in vivo situation of the intact liver. Therefore, we will stimulate the intact organ by injection of, for instance, HGF, IL6 or insulin into the portal vein. This procedure will allow comparing the dynamics of signaling in vivo and in vitro. Our Cooperation will compare the generated data with the human situation.

Magdeburg - Mannheim

Klamt - Dooley

• Subject: Modeling of TGF-ß signaling cross-talks in hepatocytes
  Details: Sharing the experimental data and software (CellNetAnalyzer) and logical signaling model of TGF-ß signaling cross-talks is generated.

Magdeburg - Tuebingen

Bannasch - Dräger/Zell

• Subject: Implementation of an access to the SBML converter in the central data management system
  Details: Andreas Dräger is one of the developers of the SBML converter, a tool that translates the information of a SBML file into a 'human readable format'. The tool has already been tested by the central data management. It appears to be very useful for both modelers and biologists. Therefore, we intend to make this tool available in the central data management system in the future. We will define together the best way to do this.

Mirschel/Gilles - Dräger/Zell

• Subject: Development of interactive modeling tools using SBML
  Details: The modeling programs SBMLsqueezer developed in Tuebingen and ProMoT developed in Magdeburg are the basis of the joint research projects. The idea is to integrate the functionality of SBMLsqueezer with ProMoT.

Mannheim - Munich

Dooley - Athelogou/Definiens

• Subject: Image analysis
  Details: On a cooperation base, adjustment of Definiens software, utilizing a new image analyzing procedure based on the information processing with the Cognition Network Language, for a quantitative analysis of single cell images was done. This software will be used for analysis of three-dimensional image sets exploring TGF-ß signaling in hepatocytes.

Dresden - Munich

Zerial - Athelogou/Definiens

• Subject: Image analysis
  Details: Analysis of experimental image data.

Bochum - Munich

McCaskill - Athelogou/Definiens

• Subject: Image analysis
  Details: Analysis of simulated image data.

• Subject: As a first attempt on the way to unite experimental data with simulation results from mprDPD, Definiens is building up an object recognition facility. Not only vesicles and their trajectories in 3D space and time are part of this recognition facility but also the recognition of budding- and fusion-events of vesicles or vesicular structures. A full genealogy of vesicles and their history is intended
  Details: Definiens gets three dimensional simulation data-streams from BioMIP and returns positions, statistics, boundary-boxes and fusion- and fission-events of 3D-objects. Furthermore the abstract bodies are extracted and returned as time-series to be visualized with standard 3D-browsers.

Heidelberg - Bochum

Kummer - McCaskill

• Subject: EndoSys
  Details: EndoSys.

Wade - McCaskill

• Subject: Upscaling of MD- and Brownian dynamics. Afterwards comparison of these results with the mesoscopic methode which was build by BioMIP.
  Details: The simulations of the endocytotic transport rely on data which are, if not known, either specifically derived from experiment or estimated from molecular calculations.

Leverkusen - Tuebingen

Schuppert - Bonin

• Subject: Exchange of data
  Details: Data from dynamic gene expression induced by statins as well as genotype - gene expression data from untreated liver samples have been delivered. They provde the baseline for the imbedding into the PKSIM-models as well as for patient stratification with respect to responder - non responder classification.

Leverkusen - Stuttgart

Schuppert - Zanger

• Subject: Delivery of gene expression and genotype data from clinical tissue samples
  Details: Data from dynamic gene expression induced by statins as well as genotype - gene expression data from untreated liver samples have been delivered. They provde the baseline for the imbedding into the PKSIM-models as well as for patient stratification with respect to responder - non responder classification.

Jena - Wurzburg

Schuster - Dandekar

• Subject: Regulatory and metabolic networks
  Details: Starting from metabolic modeling algorithms we have a long term scientific collaboration regarding all aspects of cellular networks, which profits in particular from the Hepatosys Network.

Leipzig - Munich

Nüssler - Gebhardt

• Subject: Supply of primary hepatocytes
  Details: Primary hepatocytes for subsequent cell biology studies are provided by the group of Prof. Nüssler.

LocationA - LocationB

PartnerA - PartnerB

• Subject: No subject data
  Details: No Details.

The infrastructure of HepatoSys

How to use:

• All network and platform members of HepatoSys are represented by a colored spot at their place of work. The color of the spot indicates which platform or network the working group is belonging to (see legend).

• Collaborations are represented by links (white arcs). While navigating with the mouse over the illustration (especially over spots), all established collaborations of the working group within HepatoSys can be studied.

• When clicking on a certain link, a detailed description of the collaborations are given. When hitting a certain spot, the activities (conferences, workshops etc.) of the groups working at this particular location are displayed. In addition to that the collaborations of groups belonging to different networks/platforms within the same spot are listed.
  Collaborations at the same spot and within the same network/platform are not mentioned.

• When navigating over the label 'Germany', all collaborations within HepatoSys are shown.