172 research outputs found
Some Perspectives on Network Modeling in Therapeutic Target Prediction
Drug target identification is of significant commercial interest to
pharmaceutical companies, and there is a vast amount of research done related
to the topic of therapeutic target identification. Interdisciplinary research
in this area involves both the biological network community and the graph
algorithms community. Key steps of a typical therapeutic target identification
problem include synthesizing or inferring the complex network of interactions
relevant to the disease, connecting this network to the disease-specific
behavior, and predicting which components are key mediators of the behavior.
All of these steps involve graph theoretical or graph algorithmic aspects. In
this perspective, we provide modelling and algorithmic perspectives for
therapeutic target identification and highlight a number of algorithmic
advances, which have gotten relatively little attention so far, with the hope
of strengthening the ties between these two research communities
Nonparametric Simulation of Signal Transduction Networks with Semi-Synchronized Update
Simulating signal transduction in cellular signaling networks provides predictions of network dynamics by quantifying the changes in concentration and activity-level of the individual proteins. Since numerical values of kinetic parameters might be difficult to obtain, it is imperative to develop non-parametric approaches that combine the connectivity of a network with the response of individual proteins to signals which travel through the network. The activity levels of signaling proteins computed through existing non-parametric modeling tools do not show significant correlations with the observed values in experimental results. In this work we developed a non-parametric computational framework to describe the profile of the evolving process and the time course of the proportion of active form of molecules in the signal transduction networks. The model is also capable of incorporating perturbations. The model was validated on four signaling networks showing that it can effectively uncover the activity levels and trends of response during signal transduction process
Structural modelling and robustness analysis of complex metabolic networks and signal transduction cascades
The dissertation covers the topic of structural robustness of metabolic networks on the basis of the concept of elementary flux modes (EFMs). It is shown that the number of EFMs does not reflect the topology of a network sufficiently. Thus, new methods are developed to determine the structural robustness of metabolic networks. These methods are based on systematic in-silico knockouts and the subsequent calculation of dropped out EFMs. Thereby, together with single knockouts also double and multiple knockouts can be used. After evaluation of these methods they are applied to metabolic networks of human erythrocyte and hepatocyte as well as to a metabolic network of Escherichia coli (E. coli). It is found that the erythrocyte has the lowest structural robustness, followed by the hepatocyte and E. coli. These results coincide very well with the circumstance that human erythrocyte and hepatocyte and E. coli are able to adapt to conditions with increasing diversity. In a further part of the dissertation the concept of EFMs is expanded to signal transduction pathways consisting of kinase cascades. The concept of EFMs is based on the steady-state condition for metabolic pathways. It is shown that under certain circumstances this steady-state condition also holds for signalling cascades. Furthermore, it is shown that it is possible to deduce minimal conditions for signal transduction without knowledge about the kinetics involved. On the basis of these assumptions it is possible to calculate EFMs for signalling cascades. But due to the fact that these EFMs do no longer just have mass flux but also information flux, they are now called elementary signalling modes (ESMs).Die Dissertation behandelt die strukturelle Robustheit von metabolischen Netzwerken auf der Basis des Konzepts der elementaren Flussmoden (EFMen). Es wird gezeigt, dass die Anzahl der EFMen die Topologie eines metabolischen Netzes nicht ausreichend widerspiegelt. Darauf aufbauend werden neue Methoden entwickelt, um die strukturelle Robustheit metabolischer Netze zu bestimmen. Diese Methoden beruhen auf systematischen in-silico-Knockouts und der anschließenden Bestimmung des Anteils an weggefallenen EFMen. Dabei können neben Einfach-Knockouts auch Doppel- oder Mehrfach-Knockouts verwendet werden. Nach der Evaluierung werden diese Methoden auf metabolische Netzwerke des menschlichen Erythrozyten und Hepatozyten, sowie des Bakteriums Escherichia coli (E. coli) angewendet. Es zeigt sich, dass der Erythrozyt die im Vergleich geringste strukturelle Robustheit besitzt, gefolgt vom Hepatozyten und E. coli. Diese Ergebnisse stimmen sehr gut mit der Beobachtung überein, dass sich die menschlichen Erythrozyten und Hepatozyten, sowie E. coli an zunehmend verschiedene Bedingungen anpassen können. In einem weiteren Teil der Dissertation wird das Konzept der EFMen auf Signaltransduktionswege bestehend aus Kinase-Kaskaden erweitert. Das Konzept der EFMen beruht auf der Annahme eines quasi-stationären Zustands für metabolische Netzwerke. Es wird gezeigt, dass dieser quasi-stationäre Zustand unter bestimmten Bedingungen auch in Signal-Kaskaden angenommen werden kann. Weiterhin wird gezeigt, dass man ohne Kenntnis der beteiligten Kinetiken Minimalbedingungen für die Signalweiterleitung ableiten kann. Auf Basis dieser Annahmen lassen sich für Signal-Kaskaden EFMen berechnen. Aber aufgrund der Tatsache, dass sie nicht mehr nur Masse-, sondern auch Informationsfluss beschreiben, werden sie nun als elementare Signalmoden (ESMen) bezeichnet
Using graph theory to analyze biological networks
Understanding complex systems often requires a bottom-up analysis towards a systems biology approach. The need to investigate a system, not only as individual components but as a whole, emerges. This can be done by examining the elementary constituents individually and then how these are connected. The myriad components of a system and their interactions are best characterized as networks and they are mainly represented as graphs where thousands of nodes are connected with thousands of vertices. In this article we demonstrate approaches, models and methods from the graph theory universe and we discuss ways in which they can be used to reveal hidden properties and features of a network. This network profiling combined with knowledge extraction will help us to better understand the biological significance of the system
Control of complex networks requires both structure and dynamics
The study of network structure has uncovered signatures of the organization
of complex systems. However, there is also a need to understand how to control
them; for example, identifying strategies to revert a diseased cell to a
healthy state, or a mature cell to a pluripotent state. Two recent
methodologies suggest that the controllability of complex systems can be
predicted solely from the graph of interactions between variables, without
considering their dynamics: structural controllability and minimum dominating
sets. We demonstrate that such structure-only methods fail to characterize
controllability when dynamics are introduced. We study Boolean network
ensembles of network motifs as well as three models of biochemical regulation:
the segment polarity network in Drosophila melanogaster, the cell cycle of
budding yeast Saccharomyces cerevisiae, and the floral organ arrangement in
Arabidopsis thaliana. We demonstrate that structure-only methods both
undershoot and overshoot the number and which sets of critical variables best
control the dynamics of these models, highlighting the importance of the actual
system dynamics in determining control. Our analysis further shows that the
logic of automata transition functions, namely how canalizing they are, plays
an important role in the extent to which structure predicts dynamics.Comment: 15 pages, 6 figure
Modeling Functional Modules Using Statistical and Machine Learning Methods
Understanding the aspects of the cell functionality that account for disease or drug action
mechanisms is the main challenge for precision medicine. In spite of the increasing availability of
genomic and transcriptomic data, there is still a gap between the detection of perturbations in gene
expression and the understanding of their contribution to the molecular mechanisms that ultimately
account for the phenotype studied. Over the last decade, different computational and mathematical
models have been proposed for pathway analysis. However, they are not taking into account the
dynamic mechanisms contained by pathways as represented in their layout and the interactions
between genes and proteins. In this thesis, I present two slightly different mathematical models to
integrate human transcriptomic data with prior knowledge of signalling and metabolic pathways to
estimate the Mechanistic Pathway Activities (MPAs). MPAs are continuous and individual level
values that can be used with machine learning and statistical methods to determine biomarkers for
the early diagnosis and subtype classification of the diseases, and also to suggest potential
therapeutic targets for individualized therapeutic interventions.
The overall objective is, developing new and advanced systems biology approaches to
propose functional hypotheses that help us to understand and interpret the complex mechanism of
the diseases. These mechanisms are crucial for robust personalized drug treatments and predict
clinical outcomes. First, I contributed to the development of a method which is designed to extract
elementary sub-pathways from a signalling pathway and to estimate their activity. Second, this
algorithm adapted to metabolic modules and it is implemented as a webtool. Third, the method
used to reveal a pan-cancer metabolic landscape. In this study, I analyzed the metabolic module
profile of 25 different cancer types and the method is also validated using different computational
and experimental approaches. Each method developed in this thesis was benchmarked against
the existing similar methods, evaluated for their sensitivity and specificity, experimentally validated
when it is possible and used to predict clinical outcomes of different cancer types. The research
described in this thesis and the results obtained were published in different systems biology and
cancer-related peer-reviewed journals and also in national newspapers
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