Cancer Research - Europa

DIAMONDS
Dedicated Integration and Modelling
of Novel Data and Prior Knowledge
to Enable Systems Biology
Summary
We will demonstrate the power of a systems biology
approach to study the regulatory network structure of the
most fundamental biological process in eukaryotes: the cell
cycle. An integrative approach will be applied to build
a basic model of the cell cycle in four diff erent species
including S. cerevisiae (budding yeast), S. pombe (fi ssion
yeast), A. thaliana (weed, model plant) and human cells. To
do this, a consortium has been assembled of leaders in the
fi elds of cell cycle biology, functional genomic technologies,
database design and development, data analysis and
integration technology, as well as modelling and simulation
approaches. The project combines a number of complementary
data sets toward an advanced mining and modelling
environment, designed to assist the biologist in building
and amending hypotheses, and to help the investigator
when designing new experiments to challenge these
hypotheses. By doing these simultaneously in widely diff erent
organisms, we will ensure that the tools are generally
applicable across species. By bringing together biologists,
bioinformaticians, biomathematicians and (commercial)
software developers in the design phase, we will ensure
that a user-friendly, intuitive data analysis environment is
created. The main data streams generated de novo within
the project concern transcript profi ling and proteomics
data (Y2H and TAP). These data will be complemented with
information extracted through comparative genomics, and
prior knowledge coming from literature mining (text mining
tools). The project will bring together a number of existing
technologies to build a knowledge warehouse in a relational
database designed to contain cell cycle regulatory network
information, accessible through an intuitive user platform
(GUI) with embedded modelling tools. This platform will
enable both top-down and bottom-up hypothesis-driven
research, and will serve as a basis to develop more rigorous
dynamical models for cell cycle variants.
Problem
Cell division is regulated by highly conserved genetic networks.
Occasionally the cell division machinery becomes
unstable, resulting in an uncontrolled proliferation of cells. In
humans, the uncontrolled division and growth of cells can
lead to cancer. Cell division is also at the core of biomass
production and agricultural yield. A better understanding of
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Keywords | Functional genomics | systems biology | regulatory networks | dynamical modelling |
the processes that regulate cell division is therefore of prime
importance for human health, welfare and sustainable
development. The approach taken by DIAMONDS constitutes
a pioneering step toward the application of a systems
biology approach for genetic network analysis, and as such
will contribute to the maturation of systems biology into
a general approach, complementary to the traditional geneby-gene
approach. With the rapid increase in genome
sequences, published literature and databases on proteomic
and transcriptomic data, it is obvious that integrative analysis,
bringing together various complementary data types
for the identifi cation of network motifs, should be tested
on well-defi ned biological models to assess the potential of
a systems biology approach.
Aim
The overarching objective of this multidisciplinary project is
to demonstrate the power of a systems biology approach to
study fundamental biological processes. We focus on eukaryotic
cell cycle regulation, and will develop and implement
a computational model that will function as a hypothesisgenerating
engine in a systems biology ‘wet-lab’ environment.
The work will be done in a number of wet-labs and dry labs,
on yeast, plant and human cells, to make sure that the
approach is validated across widely diff erent organisms. The
main target of the project consists of two parts:
• a cell cycle knowledge base and an integrated platform
of data mining, modelling and simulation tools that will
allow the integrated analysis of that data in a systems
biology approach;
• the development of a basic model, the use of this model
to design new experiments, the production and analysis
of novel data, and the integration of these into a refi ned
model.
The knowledge base and tools will be made available and
introduced to the European research community.
The principle method to reach this target is to harvest and/
or produce a large body of cell cycle-related biological
knowledge. This will function as the central resource for the
modelling and simulation environment that will be developed.
As mentioned above, the knowledge warehouse will
constitute one of the major deliverables of the project, enabling
future hypothesis-driven research. The project will
showcase the fact that a systems biology approach towards
analysis of a fundamental biological process can in fact
become mature today, and hinges on an integrated data
analysis pipeline, extended with modelling and simulation
tools. The essential elements of such a pipeline will be:
functional genomics data production (transcriptome and
proteome); literature mining; comparative analysis of genes
and networks; a visualisation, modelling and simulation environment,
and a web service-based data integration layer.
CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME