- Funding Period:
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2010 - 2015
- Project description:
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Apoptosis is essential for development and survival of complex organisms. It is also called programmed cell death and gives the opportunity to remove redundant or defective cells. Dysfunctions of this process can lead to severe diseases such as cancer or neurodegeneration. Apoptosis is a research object for years now, but there are still a lot of open questions. There is a strong interest to gain further knowledge about this essential process and also to use these findings for the development of new drugs. In collaboration with our experimental partners we model pro- and antiapoptotic signaling in Hepatocytes which are the main cell type in the liver. Therefore, we use two different modeling approaches to tackle different questions.
We designed and further develop a comprehensive model of the complex apoptotic signaling network using a Boolean modeling approach. Here, we study the impact of e.g. Fas ligand, TNF alpha, UV irradiation, IL1beta, insulin and glucagon on apoptosis. The logical model allows us to analyze the topology of the network and especially to reveal biological crosstalks between different signaling pathways. We also work on improving modeling techniques and experimental design for Boolean models.
To focus on some notably questions we develop kinetic models based on ordinary differential equations. These models are more elaborate but deliver information about the dynamic behavior of the signaling pathways under research and about system properties such as stability. Here, we concentrate on Fas ligand and TNFalpha signaling and the crosstalk of these two pathways. Thereby, also NF-kappaB signaling is involved. We are especially interested in the type I/type II apoptosis switch.
In addition, we also study the interaction between Hepatocytes and macrophages. Activation of liver macrophages (also termed Kupffer cells) is known to mediate important hepatoprotective effects and advocates liver regeneration but also plays a substantial role for mediation of liver injury in response to e.g. hepatotoxic substances or microbial pathogens. Macrophage derived chemokines and cytokines such as TNFalpha or IL1beta are crucial mediators of hepatotoxicity and contribute to inflammation induced impaired hepatocyte functionality. Thereby, the macrophage ‘input’ into hepatocyte action is differentiation dependent. We are working towards the definition of macrophage derived key mediators or mediator patterns, the knowledge of critical feedback loops that govern this reciprocal relationship between macrophage differentiation and hepatocyte response and the development of a comprehensive pathway model of intracellular signaling networks activated in hepatocytes that translates the macrophage ‘input’ into a hepatocyte response.
Partner:
A.2.2: Regulation of proapoptotic and antiapoptotic responses in hepatocytes
- Albert Ludwigs University Freiburg
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Institute of Molecular Medicine and Cell Research Center of Biochemistry and Molecular Cell Research (ZBMZ): Christoph Borner
- Albert Ludwigs University Freiburg
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Institute of Pharmaceutical Sciences Department of Pharmaceutical Biology and Biotechnology: Irmgard Merfort
- Heinrich Heine Universität Düsseldorf
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Klinik für Gastroenterologie, Hepatologie und Infektiologie: Johannes Bode
- University of Freiburg
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Institute of Physics: Jens Timmer
- University of Stuttgart
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Institute for System Dynamics, CSB: Oliver Sawodny, Michael Ederer
B.1: Intercellular communication of hepatocytes and macrophages
- Albert Ludwigs University Freiburg
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Institute of Molecular Medicine and Cell Research Center of Biochemistry and Molecular Cell Research (ZBMZ): Christoph Borner
- German Cancer Research Center (DKFZ)
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Division Systems Biology of Signal Transduction: Ursula Klingmüller
- Heinrich Heine Universität Düsseldorf
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Klinik für Gastroenterologie, Hepatologie und Infektiologie: Johannes G. Bode
- University of Freiburg
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Institute of Physics: Jens Timmer
- University of Stuttgart
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Institute for System Dynamics, CSB: Oliver Sawodny, Michael Ederer