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• W2890826811 abstract "Author(s): Gutierrez Bugarin, Jahir Mauricio | Advisor(s): Lewis, Nathan E; Palsson, Bernhard O | Abstract: The secretory pathway is a fundamental process of eukaryotic cells and it is responsible for synthesizing, folding, and packaging thousands of membrane and secreted proteins. These proteins play important roles in cells as signaling molecules, hormones, receptors, and structural components. Today, many of the most important biotherapeutics and monoclonal antibodies are produced via the secretory pathway of animal cells in culture. Thus, it has become clear that a mechanistic understanding of the function and regulation of the secretory pathway is of prime importance for the advancement of biotechnology and bioprocessing. In this doctoral dissertation, computational methods are developed and applied to quantify the energetic burden that the secretory pathway imposes on animal cell metabolism at the systems level. First, a meta-analysis workflow to extract quantitative features from the cell bioprocessing literature is presented. These quantitative features are consistent across studies and culture conditions and thus provide insight into fundamental properties of cell bioprocessing. Second, genomic and proteomic data are utilized to construct genome-scale computational reconstructions of the human, mouse, and Chinese hamster secretory pathways. These reconstructions are used to expand the scope of existing genome-scale metabolic networks and to investigate the energetic trade-off between cellular growth and protein secretion during bioprocessing. Model simulations recapitulate bioprocess measurements and enable the quantification of energetic costs associated to cellular productivity in a product-specific manner. Finally, a mathematical expression for computing the energetic cost of protein synthesis is formulated and used to map the energetic cost landscape of a cell secretome. The energetic cost of proteins negatively correlates with protein expression levels and this negative correlation is stronger in highly secretory animal cell lines and human tissues. Finally, protein turnover rates are used to investigate the robustness and usage levels of the secretory pathway across human tissues. The degree of secretory pathway usage is linked to the degradation rate of the half-lives of secretory pathway components in a modular manner that is shaped by the product-specific demands of the secreted proteins in each cell type. The results from this analysis may help design strategies for engineering the secretory pathway in CHO cells." @default.
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• W2890826811 date "2018-01-01" @default.
• W2890826811 modified "2023-09-27" @default.
• W2890826811 title "Systems Biotechnology of the Mammalian Secretory Pathway: Analysis of Energetic Trade-offs in Protein Production" @default.
• W2890826811 hasPublicationYear "2018" @default.
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