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Inference and Study of Immune Network Biology in a Complex Stress-mediated Illness
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- Author / Creator
- Vashishtha, Saurabh
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Gulf War Illness (GWI) is a complex debilitating condition presenting with a diverse array of symptoms that include fatigue, memory and cognitive difficulties, headaches, sleep disturbances, gastrointestinal problems, skin rashes, as well as musculoskeletal/joint pain. It affects up to one third of the US veterans returning from the 1991 Persian Gulf conflict (Operation Desert Storm). The overarching objective of this study is to integrate clinical understanding of the disease with basic research in molecular medicine using a systems biology approach to pinpoint underlying mechanisms of disease and inform treatment more effectively.In the first part of this thesis, we survey several popular reverse engineering methods for inferring directed networks from time course data and assess their suitability to the narrow range of conditions and low sampling frequencies typical of human clinical studies. Based on this assessment we develop a novel variant of such methods that leverages simulations of biologically realistic artificial networks to optimize the recovery of actual biological networks from data in a problem-specific manner. Using this simulation-based tuning approach we identify and extract candidate immune signaling patterns, which are then filtered by projecting onto a literature-informed mechanistic model of immune regulation. This literature-informed data mining identified characteristically active feed-forward mechanisms connecting IL-23 and IL-17 through IL-6 and IL-10 as distinguishing control elements in GWI. Furthermore, simulations of an IL-6 receptor antagonist applied in combination with either a Th1 (IL-2, IFNγ, TNFα) or IL-23 receptor antagonist predicted a partial rescue of immune response circuitry in GWI.To support the in vivo testing of these in silico predictions, the last part of this thesis is directed at establishing the mechanistic similarity of the human GWI conditioniiiwith a stress-potentiated response to neurotoxic exposure in mouse. In support of this, undirected networks were constructed linking 12 cytokines measured in peripheral blood in mice challenged with Lipopolysaccheride (LPS) after exposure to the sarin surrogate DFP (Diisopropyl fluorophosphates) under conditions of simulated stress induced by corticosterone (CORT) doping of their drinking water. An evolutionarily conserved GWI- specific motif linking IL-6, IL-8, IL1β, TNF-α, IL-5 and IFN-γ was identified supporting the alignment of mouse and human cytokine co-expression networks. Collectively this thesis proposes a network identification methodology which is robust to the limitations of human data, testable hypotheses supporting the partial recovery of immune signaling networks in GWI-affected veterans and the network informed validation of an animal model in which such hypotheses might be explored in vivo.
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- Graduation date
- Spring 2019
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- Type of Item
- Thesis
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- Degree
- Doctor of Philosophy
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- License
- Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.