Applications of Protein-Constrained Genome-Scale Modelling for Strain Design and Context-Specific Metabolic Prototyping in Synthetic Biology
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Authors
Yao, Herbert
Date
Type
thesis
Language
eng
Keyword
Genome-scale modelling , Systems Biology , Optimization , Synthetic biology
Alternative Title
Abstract
Genome-scale modelling (GEM) has been a research interest and a potent tool in cell-level modelling for decades. Among all studies that uses GEM, the simplest genome-scale metabolic model (M-model) is used in the vast majority of cases due to its accessibility in published models and algorithms, despite having clear limitations. Incorporating protein constraints to M-model greatly mitigates some of its limitations, yet there is little consensus regarding the formulation and algorithms for the resulting metabolic model with protein constraints (PC-model). In this thesis, we are proposing a toolbox specifically for building PC-model and tailoring algorithms for it, with an ultimate goal of building a new PC-model community that can enhance the accuracy of in-silico experiment through GEM.
In Chapter 2, we introduce a new method, OVERLAY, to decipher the metabolism of the cell for a given transcriptome measurement using PC-model. This is accomplished in three main phases: first, a computational pipeline is developed to incorporate the published M-model with the enzyme information of the cell to produce a PC-model; second, the protein level is constrained by the experimental gene expression data through solving a two-step quadratic optimization, resulting in a context-specific PC-model; last, the context-specific PC-model is explored using flux variability analysis. In a case study, OVERLAY is proven proficient in decoding cellular metabolism and suggesting metabolic reprogramming strategies.
In Chapter 3, we adapted several algorithms (minimal cell, PC-OptKnock, MOPA, PC-dynamicFBA) that was designed for M-model into the appropriate form for PC-model, some with boosted utilities. These algorithms are all for strain design and metabolic engineering purposes, and we believe they would synergize well with OVERLAY to exploit the potential of PC-model as a tool for simulating biochemical productions and biotechnology.
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Queen's University's Thesis/Dissertation Non-Exclusive License for Deposit to QSpace and Library and Archives Canada
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Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.
Attribution 3.0 United States
ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.
Attribution 3.0 United States