Exploring the spatio-temporal dynamics of lipid rafts and their role in signal transduction

Haack, Fiete (2016) Exploring the spatio-temporal dynamics of lipid rafts and their role in signal transduction. PhD thesis, Institute of Computer Science, University of Rostock.

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Modeling and simulation of signal transduction pathways facilitate the integration of ex- perimental knowledge into a coherent picture and is increasingly regarded as a valuable complement to wet-lab experiments. However, despite its importance, the implications of space (e.g. diffusion, molecular crowding or active transport) have traditionally been neglected in common models of signal transduction. Seizing on this problem, the aim of this thesis is to elucidate the biological as well as methodological implications that arise from modeling the spatio-temporal dynamics of lipid rafts, particularly in the context of signal transduction. Lipid rafts are small, dynamic structures that are crucially involved in the spatial organization of the cell membrane, hence play a central role in signaling. Notably, lipid rafts are involved in almost all central physiology-related signaling path- ways and are associated with a continuously growing list of diseases, including immune disorders, degenerative diseases and cancer. Though, the actual impact of lipid rafts on downstream signaling components and their exact role in the majority of signaling pathways is still largely unknown. Therefore the effect of raft-dependent receptors dynamics on both, individual signal- ing events as well as an entire signaling transduction pathway, is explicitly analyzed here. First, a Cellular-Automata based membrane model is developed to explore the effect of lipid rafts on individual signaling events, such as the association of peripheral proteins to membrane-integral receptors and the subsequent formation of a ternary re- ceptor complex. After that, the specific involvement of lipid rafts in Wnt/ β -catenin signaling during neural differentiation is explored by means of an integrated in silico and in vitro approach. Accordingly, based on experimental data retrieved from human neural progenitor cells an extended model of the canonical Wnt signaling pathway in- cluding membrane-related processes and lipid rafts is developed. However, the level of abstraction, i.e. the spatial scale required to describe certain as- pects of spatial membrane dynamics, strongly depends on the subject of interest, the concrete addressed scientific questions and eventually on the experimental data avail- able. Therefore a particular focus is laid on the close interplay between the formal representation of cellular or subcellular dynamics and experimental investigation.

Item Type: Thesis (PhD)
Projects: ESCeMMo