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The Chemical and Computational Biology of Inflammation

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The Chemical and Computational Biology of Inflammation The chemical and computational biology of inflammation A thesis submitted to the University of Manchester for the degree of Ph.D. in the Faculty of Engineering and Physical Sciences 2011 Ben Small Doctoral Training Centre Integrative Systems Biology Molecules to Life within the School of Chemical Engineering and Analytical Science Table of Contents Title Page………………………………………………………………………………1 Table of Contents ........................................................................................................... 2 List of Figures ................................................................................................................ 3 Abbreviations and Symbols ........................................................................................... 4 Abstract .......................................................................................................................... 9 Lay Abstract – ‘Sifting drug combinations to treat disease’ ........................................ 10 Declaration ................................................................................................................... 11 Copyright Statement .................................................................................................... 11 Acknowledgements ...................................................................................................... 12 Preface and Quotes ....................................................................................................... 14 Chapter 1 Introduction…………………………………………………………………. 15 1.1 Inflammation: a central problem for medicine................................................. 15 1.2 Interleukin-1; a pro-inflammatory cytokine ..................................................... 17 1.2.1 The release of IL-1 ....................................................................................... 18 1.3 Toll-like receptor 4 and the synthesis of IL-1β ................................................ 20 1.3.1 Consideration of the TLR4 signaling network ............................................. 21 1.5 Inflammatory transformation of tissues: an issue of robustness ...................... 24 1.6 Systems biology a definition and its impact in innate immunity ..................... 25 1.7 The Problem ..................................................................................................... 27 1.8 The Question .................................................................................................... 28 1.9 An Introduction to evolutionary computation .................................................. 29 1.10 A biochemists guide to In silico modeling of biochemical systems ................ 32 1.11 Combinatorial solutions to complex problems? ............................................... 36 1.12 Aims and objectives ......................................................................................... 36 Chapter 2…………………………………………………………………………………..38 Publication number: 01 Efficient discovery of anti-inflammatory small molecule combinations using evolutionary computing ....................................................................... 38 Chapter 3 Analysis of the LPS directed signaling network ………………………….39 3.1 Introduction………………………………………………………………. 39 3.2 Network map construction………………………………………………...40 Chapter 4…………………………………………………………………………………..41 Publication number: 02 A network map of lipopolysaccharide-dependent IL-1β expression in macrophages and monocytes ......................................................................... 41 Chapter 5 Discussion ........................................................................................................ 42 5.1. Introduction .......................................................................................................... 42 5.2 Efficient discovery of anti-inflammatory drug combinations using evolutionary computing ......................................................................................................................... 42 5.3 A network map of lipopolysaccharide dependent IL-1β expression in macrophages and monocytes............................................................................................ 46 5.4 Conclusion ........................................................................................................... 46 5.5 Back to the future ................................................................................................. 47 5.6 Future work .......................................................................................................... 47 5.6.1 Mixed messages: drug efficacy…………………………………………………48 Bibliography ........................................................................................................ 50 Word count: 18351 2 List of Figures Figure 1.1 A wordle generated from the extracted text of reviews on the science of 28 systems biology presented above. Figure 1.2 The basic principles behind the workings of evolutionary algorithms. 32 Figure 1.3 An idealized uni-molecular reaction detailing the conversion of species 34 A into B with corresponding mass fluxes ( Γ). Figure 1.4 Simulation of the uni-molecular reaction A = B (outlined in Figure 1.3) 37 performed in COPASI. 3 Abbreviations and Symbols ∆∆∆G Gibbs free energy ΓΓΓ Mass flux ∞∞∞ Infinity µµµ micro (10 -6 of quantity) µµµg microgramme µµµM micromolar µµµL microlitre ο C degrees celsius [nX] Heavy atom; where n is mass number and X is the element labelled A xxxnm Absorbance measured at a given 'xxx' wavelength in nm A20 Tumor necrosis factor alpha-induced protein 3 Ab Antibody AIM2 Absence In Melanoma receptors Akt v-akt murine thymoma viral oncogene homolog AlogP Atomic contribution calculation of Partition coefficient AMS Academy of Medical Sciences ANOVA Analysis Of VAriance ASC Apoptosis-associated Speck-like protein containing a CARD ASK1 Apoptosis Signal regulating Kinase 1 ATP Adenine TriPhosphate BBSRC Biotechnology and Biological Sciences Research Council BMS345541 (4(2 ′-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline) bZIP basic leucine ZIPper domain 2+ [Ca ]i Intracellular calcium concentration cAb Capture Antibody CAPS Cyropyrin Associated Periodic Syndromes CARD CAspase Recruitment Domain CAT ChlorAmphenicol Transferase CDX Cluster of Differentiation (where X is the subtype of this molecule) cDNA Complementary DeoxyriboNucleic Acid C/EBP-βββ CAAT Enhancer Binding Protein-beta ChEMBL a database of bioactive drug-like small molecules hosted by EMBL ChIP Chromatin ImmunoPrecipitation CLR C-type Lectin Receptors CIAS1 Cold Induced Autoinflammatory Syndrome 1 gene (Human) CIITA Class II, major histocompatibility complex, TransActivator gene (Human) CKII Casein Kinase II CO 2 Carbon dioxide COPASI Complex Pathway SImulator COPD Chronic Obstructive Pulmonary Disease CREBP cAMP Response Element Binding Protein CSBP Cytokine Supressive anti-inflammatory Binding Protein CSP CAP Site Proximal dAb Detection Antibody DAMP Danger Associated Molecular Patterns DECTIN-1 C-type lectin domain family 7, member A DMEM Dulbecco’s Modified Eagle Medium DMSO DiMethyl SulphOxide DNA DeoxyriboNucleic Acid 4 DTC Doctoral Training Centre - Integrative Systems Biology Molecules to Life DUSP1 / MKP-1 DUal Specificity Phosphotase 1 / MAPK Phosphotase 1 EA (Multi-Objective) Evolutionary Algorithm EGCG Epigallocatechin Gallate ELISA Enzyme Linked Immunosorbant Assay EMBL European Molecular Biology Laboratory EPSRC Engineering and Physical Sciences Research Council ERK Extracellular signal-Regulated Kinases FBS / FCS Foetal Bovine Serum / Foetal Calf Serum g times gravity (x g: units of relative centrifugal force) GA Genetic Algorithm GSK3 Glycogen Synthase Kinase 3 GST Glutathione-S-Transferase GTPase Guanine Tri Phosphotase h hours HBA Hydrogen Bond Acceptor HBD Hydrogen Bond Donor HETE HydroxyEicosaTetraEnoic acid HMGB1 High Mobility Group Box 1 HMG-CoA 3-hydroxy-3-methyl-glutaryl-CoA reductase reductase HSE Heat Shock Element HSF1 Heat Shock Factor 1 IBEA Indicator Based Evolutionary Algorithm IC 50 The concentration of a reagent at which the 50 % of the effect / response is inhibited. IFN-βββ Interferon-β IKKi BMS345541 (see abbreviation) IKKX Inhibitor of Kappa B Kinase (where the suffix X represents a subtype of this kinase) IL Interleukin IL-1 Interleukin-1 IL-6 Interleukin-6 IL-10 Interleukin-10 IL-1ααα Interleukin-1 Alpha (also ILF1) IL-1βββ Interleukin-1 Beta (also ILF2) IL1B Interleukin-1 Beta gene (Human) il1b Interleukin-1 Beta gene (Mouse) IL-1RA Interleukin-1 Receptor Antagonist IL-1RAcP Interleukin-1 Receptor Accessory Protein IL-1RI Interleukin-1 Receptor I IL-1RII Interleukin-1 Receptor II IL-F11 Interleukin-33 IRAKX Interleukin-1 Receptor Associated Kinase (where the suffix X represents a subtype of this kinase) IRF3 Interferon Regulated Factor 3 IRF4 Interferon Regulated Factor 4 IRF8 Interferon Regulated Factor 8 IκκκBααα Inhibitor of Kappa B alpha J Concentration flux JNK c-jun N-terminal Kinase k Rate constant kDa kiloDalton 5 K + Potassium ion LAF Leuckocyte Activating Factor LBP Lipopolysaccharide Binding Protein LDH Lactate DeHydrogenase LILRE LPS and IL-1 Responsive Element log 10 Logarithm to the base 10 LP Leukocytic Pyrogen LPS LipoPolySaccharide LRR Leucine Rich Repeats LY294002 2-morpholin-4-yl-8-phenylchromen-4-one MAL MyD88 Adaptor Like MAP2K Mitogen Activated Protein Kinase Kinase MAP3K Mitogen Activated Protein Kinase Kinase Kinase MAPK14 p38 α MAPK MAPK Mitogen Activated Protein Kinase MAPKK Mitogen Activated Protein Kinase Kinase MAPKKK
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