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Title: Mathematical models of cellular decisions : investigating immune response and apoptosis
Author: Harrington, Heather Anne
ISNI:       0000 0004 2692 0331
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2010
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The main objective of this thesis is to develop and analyze mathematical models of cellular decisions. This work focuses on understanding the mechanisms involved in specific cellular processes such as immune response in the vascular system, and those involved in apoptosis, or programmed cellular death. A series of simple ordinary differential equation (ODE) models are constructed describing the macrophage response to hemoglobin:haptoglobin (Hb:Hp) complexes that may be present in vascular inflammation. The models proposed a positive feedback loop between the CD163 macrophage receptor and anti-inflammatory cytokine interleukin-10 (IL-10) and bifurcation analysis predicted the existence of a cellular phenotypic switch which was experimentally verified. Moreover, these models are extended to include the intracellular mediator heme oxygenase-1 (HO-1). Analysis of the proposed models find a positive feedback mechanism between IL-10 and HO-1. This model also predicts cellular response of heme and IL-10 stimuli. For the apoptotic (cell suicide) system, a modularized model is constructed encompassing the extrinsic and intrinsic signaling pathways. Model reduction is performed by abstracting the dynamics of complexes (oligomers) at a steady-state. This simplified model is analyzed, revealing different kinetic properties between type I and type II cells, and reduced models verify results. The second model of apoptosis proposes a novel mechanism of apoptosis activation through receptor-ligand clustering, yielding robust bistability and hysteresis. Using techniques from algebraic geometry, a model selection criterion is provided between the proposed and existing model as experimental data becomes available to verify the mechanism. The models developed throughout this thesis reveal important and relevant mechanisms specific to cellular response; specifically, interactions necessary for an organism to maintain homeostasis are identified. This work enables a deeper understanding of the biological interactions and dynamics of vascular inflammation and apoptosis. The results of these models provide predictions which may motivate further experimental work and theoretical study.
Supervisor: Buck, Dorothy Sponsor: National Science Foundation Graduate Research Fellowship ; Imperial College
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral