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Title: Quantitative analysis of cellular perception in eukaryotic signalling networks
Author: Granados Castro, Alejandro Adrian
ISNI:       0000 0004 6422 7597
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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Organisms must detect changes in the environment, integrate information from multiple sources, and make informed decisions about how to use resources to respond and adapt. At the cellular level, information is sensed and processed by signalling networks that coordinate sensory information with physiological responses such as regulation of gene expression. Complex phenotypes such as cellular differentiation and disease states derive from decision making processes and depend on whether information is processed correctly. In order to address this complexity, it is necessary to consolidate the molecular mechanisms that process information into an integrative framework. While substantial research has been conducted on each of cellular signalling and gene regulation, a quantitative framework to understand the information flow is still missing. Perception, as defined for humans, comprises fundamental concepts of information processing: identification, organization, representation and interpretation. Here we argue that we can represent the flow of information in cellular systems by developing a framework of cellular perception. In general terms, information has to be sensed and internalized by signalling networks before it can be encoded into internal variables that cells can use to represent the environment. We thus investigate the molecular mechanisms by which cells sense and encode information in the single-cell microbe Saccharomyces cerevisiae as an example organism. In S. cerevisiae, as in all eukaryotes, a main mechanism to regulate gene expression is the dynamic nuclear translocation of transcription factors. We develop a framework of cellular perception in the context of dynamic nuclear translocation by characterizing the sensing and encoding of information necessary to accurately map environmental conditions to specific cellular responses. By investigating the sensing mechanisms of the hyperosmolar glycerol (HOG) MAPK network, we showed how this network improves sensing of dynamic signals by having two specialized input pathways. For the encoding mechanisms, we showed that the dynamic roles of nuclear translocation of transcription factors can function as highly informative intracellular variables. As these internal variables can encode both the magnitude and identity of the stress signal, they can be used by the cell to accurately represent the environment and determine the specific physiological responses. This thesis provided a solid ground for quantitative research in the field of cellular signalling and gene regulation. Moreover, the methods and experimental approaches applied here are broadly applicable in other organisms.
Supervisor: Tanaka, Reiko Sponsor: Engineering and Physical Sciences Research Council ; Consejo Nacional de Ciencia y Tecnología
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral