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Regulatory control networks of synthetic lethality

Objective

This project addresses robustness of phenotypic function on the basis of highly interlinked network topologies on a very practical level: Synthetic Lethality - as proposed for novel cancer treatment regimes. Function in this context is the property of transformed cells to continuously divide, and robustness is encoded by regulatory elements on the genomic and proteomic level triggering drug treatment escape as an emergent property: chemotherapy resistance.

This project will derive novel concepts, methodologies, and their algorithmic implementation for annotation and analysis of general regulatory networks - with particular focus on network robustness and escape routes toward maintaining function. In parallel, computational genomics will be applied on a gene expression data set derived from a unique, systematic collection of chemotherapy resistant cancer cell lines. These real world data encode a set of regulatory escape mechanisms to overcome the lethality imposed by specific drug.

The general concepts and approaches - focusing on dynamical levels - will subsequently be calibrated and merged with results from computational genomics - focusing on a static system representation - to gain insight into the mechanisms of cancer cell robustness, but in particular to identify key proteins of cellular escape mechanisms to overcome lethality of drugs. Blocking these proteins may result in synthetic lethality including re-sensitization of chemoresistant cancer cells to cytotoxic drugs.

To prove the validity of our Complex Systems Analysis approach we will test generated hypotheses on synthetically lethal hubs in the cellular control network via experimental knock down experiments utilizing siRNA. This project will provide further insight into dynamical hierarchies of structure and control on a general level, will calibrate methodologies for their use in computational biology, and will test the validity of these approaches for identifying novel routes in cancer treatment.

Field of science

  • /engineering and technology/electrical engineering, electronic engineering, information engineering/information engineering/telecommunications/telecommunications network
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins
  • /natural sciences/mathematics/pure mathematics/topology
  • /medical and health sciences/clinical medicine/cancer

Call for proposal

FP6-2005-NEST-PATH
See other projects for this call

Funding Scheme

STREP - Specific Targeted Research Project

Coordinator

FRAUNHOFER-GESELLSCHAFT ZUR FÖRDERUNG DER ANGEWANDTEN FORSCHUNG E.V.
Address
Hansastrasse 27C
München
Germany

Participants (6)

EMERGENTEC BIODEVELOPMENT GMBH
Austria
Address
Rathausstrasse 5/3
Vienna
UNIVERSITAT POMPEU FABRA
Spain
Address
Merce, 10-12
Barcelona
WEIZMANN INSTITUTE OF SCIENCE
Israel
Address
Herzl 1
Rehovot
BLUE-DRUGS
Germany
Address
Komturstrasse 3A
Frankfurt Am Main
KLINIKUM DER JOHANN WOLFGANG GOETHE UNIVERSITÄT
Germany
Address
Theodor Stern Kai 7
Frankfurt Am Main
UNIVERSITÄT LEIPZIG
Germany
Address
Ritterstrasse 29
Leipzig