Methods for construction and analysis of computational models in systems biology : applications to the modelling of the heat shock response and the self-assembly of intermediate filaments

摘要

Systems biology is a new, emerging and rapidly developing, multidisciplinaryresearch field that aims to study biochemical and biological systems froma holistic perspective, with the goal of providing a comprehensive, system-level understanding of cellular behaviour. In this way, it addresses one ofthe greatest challenges faced by contemporary biology, which is to compre-hend the function of complex biological systems. Systems biology combinesvarious methods that originate from scientific disciplines such as molecu-lar biology, chemistry, engineering sciences, mathematics, computer scienceand systems theory. Systems biology, unlike “traditional” biology, focuseson high-level concepts such as: network, component, robustness, efficiency,control, regulation, hierarchical design, synchronization, concurrency, andmany others. The very terminology of systems biology is “foreign” to “tra-ditional” biology, marks its drastic shift in the research paradigm and itindicates close linkage of systems biology to computer science.One of the basic tools utilized in systems biology is the mathematicalmodelling of life processes tightly linked to experimental practice. The stud-ies contained in this thesis revolve around a number of challenges commonlyencountered in the computational modelling in systems biology. The re-search comprises of the development and application of a broad range ofmethods originating in the fields of computer science and mathematics forconstruction and analysis of computational models in systems biology. Inparticular, the performed research is setup in the context of two biolog-ical phenomena chosen as modelling case studies: 1) the eukaryotic heatshock response and 2) the in vitro self-assembly of intermediate filaments,one of the main constituents of the cytoskeleton. The range of presentedapproaches spans from heuristic, through numerical and statistical to ana-lytical methods applied in the effort to formally describe and analyse thetwo biological processes. We notice however, that although applied to cer-tain case studies, the presented methods are not limited to them and canbe utilized in the analysis of other biological mechanisms as well as com-plex systems in general. The full range of developed and applied modellingtechniques as well as model analysis methodologies constitutes a rich mod-elling framework. Moreover, the presentation of the developed methods, their application to the two case studies and the discussions concerningtheir potentials and limitations point to the difficulties and challenges oneencounters in computational modelling of biological systems. The problemsof model identifiability, model comparison, model refinement, model inte-gration and extension, choice of the proper modelling framework and levelof abstraction, or the choice of the proper scope of the model run throughthis thesis.