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The Role of Abcb1 and Abcb5 in Paediatric Inflammatory

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The Role of Abcb1 and Abcb5 in Paediatric Inflammatory THE ROLE OF ABCB1 AND ABCB5 IN PAEDIATRIC INFLAMMATORY BOWEL DISEASE Thesis submitted in accordance with the requirements of the University of Liverpool NOVEMBER 2018 THE UNIVERSITY OF LIVERPOOL Wolfson Centre for Personalized Medicine Department of Clinical and Molecular Pharmacology Institute of Translational Medicine, University of Liverpool And Alder Hey Children’s Hospital NHS Foundation Trust Research Work by Doctor Anastasia Konidari Consultant Paediatric Gastroenterologist Alder Hey Children’s Hospital NHS Foundation Trust Abstract ABC transporters play an important role in drug disposition. ABCB1, the most studied representative member of this transporter superfamily, can influence drug response and shape multi-drug resistance in cancer and various diseases including inflammatory bowel disease. Adult studies have shown inter-individual variability in expression between patients with inflammatory bowel disease and healthy controls, which can be modified by corticosteroid administration, a common treatment agent for inflammatory bowel disease. ABCB5 is a novel transporter highly homologous to ABCB1. This thesis focusses on an inception pilot cohort of children and young people with newly diagnosed inflammatory bowel disease and healthy controls. The purpose of this thesis is to investigate the expression of ABCB1 and ABCB5 in vitro and ex vivo, to test the hypothesis that both are important in children with inflammatory bowel disease with respect to expression, to investigate how expression varies with genotype, and to explore the possible role of ABCB5 as corticosteroid transporter. De novo production of stable and transient overexpressing mammalian ABCB5 clones confirmed high gene expression at the mRNA level, but no ABCB5 protein isoforms were detectable, despite repeated attempts and investigation of human malignant cell derived ABCB5 expressing clones donated by experts in the field. Radiolabeled drug uptake studies with corticosteroids commonly implemented in the treatment of inflammatory bowel disease, showed that corticosteroid efflux was not mediated by any of the ABCB5 overexpressing mammalian cell lines. Children with newly diagnosed inflammatory bowel disease and healthy controls recruited at a regional tertiary children’s hospital were genotyped for common ABCB1 and novel ABCB5 single nucleotide polymorphisms. The genotype variation observed between cases and controls was not statistically different at the point of diagnosis. The minor allele frequency for rs2032582 (G2677T in exon 21 of the ABCB1 gene) was significantly different between cases and controls (p=0.01), but this did not withstand correction for multiple testing. ABCB1 and ABCB5 gene expression profiling of blood and intestinal biopsies from 16 patients with inflammatory bowel disease and 20 controls was determined. No significant variability was observed in ABCB1 gene expression across ABCB1 genotypes or clinical phenotypes (inflammatory bowel disease versus healthy state). ABCB5 expression was not detectable in blood or intestinal biopsies taken from the small intestine and sigmoid colon of the study participants. ABCB1 and ABCB5 protein expression was characterized by immunohistochemistry in intestinal biopsies from study participants. ABCB1 showed inter and intra- individual variability in expression across blood samples and intestinal biopsies from cases and controls, but this was not significantly different. There was significant correlation between gene expression and protein expression in sigmoid colon (p=0.007). Non-specific background staining for ABCB5 by immunohistochemistry was noted, which did not allow for reliable quantification of ABCB5 protein expression in the small intestine and sigmoid colon. Treatment response to 1 corticosteroids in a subgroup of patients with ulcerative colitis showed weak correlation with ABCB1 expression. In conclusion, in this pilot set of experiments, no difference was identified in ABCB1 and ABCB5 expression at mRNA and protein level in peripheral blood cells, small intestine and colonic biopsies, taken from children with inflammatory bowel disease and healthy controls. The study was limited by the small sample size; further studies will be needed for confirmation of these results. Importantly, there was no ABCB5 expression at the protein level and no functional activity was identifiable with respect to corticosteroid efflux in transfected cell lines. Further work is required to appreciate the role of ABCB5 in intestinal physiology and pathology. 2 Acknowledgements This academic journey commenced in 2012 and ended in 2018. I would like to express my deep gratitude to Professor Sir Munir Pirmohamed and Doctor David Dickens for their continuous support and guidance. People who have helped in this piece of work are Doctor Eunice Zhang, Mister George Chiduza, Doctor Fabio Miyajima, Mister David Delaney, Doctor Rajeev Shukla Consultant Pathologist and Doctor William Simmonds, Senior Registrar in Histopathology at Alder Hey Children’s Hospital. This piece of work has been conducted in partnership with the wonderful Alder Hey Gastroenterology Team that I have had the pleasure and honor to be part of, as a junior doctor, clinical research fellow, sub-specialty registrar and Consultant. I would like to thank Doctors Mark Dalzell and Marcus Auth, Consultant Paediatric Gastroenterologists at Alder Hey Children’s Hospital, who believed in this original piece of work and supported me at the start of this research journey. This is the first thesis undertaken in collaboration with the Alder Hey Paediatric Gastroenterology Department. I would like to thank my dear husband Adonis and my beloved sons Manthos and Yiannis for their patience and resilience. I dedicate this thesis to my father Yannis and my mother Effie, as a small token of my gratitude for their unconditional love, tremendous support and relentless encouragement to this day. 3 Table of Contents ABSTRACT ...........................................................................................................1 ACKNOWLEDGEMENTS .............................................................................................3 TABLE OF CONTENTS ..............................................................................................4 List of Figures ......................................................................................................8 List of Tables ......................................................................................................12 ABBREVIATIONS USED IN THIS THESIS .........................................................................23 CHAPTER 1 ..........................................................................................................1 GENERAL INTRODUCTION .........................................................................................1 1.1 OVERVIEW AND NATURE OF IBD .................................................................................3 1.1.1. Aetiology of IBD ............................................................................................4 1.2 PATHOGENESIS OF IBD ........................................................................................7 1.2.1. Environmental factors ....................................................................................7 1.2.2. Genetic susceptibility ...................................................................................12 1.3 CHILDHOOD ONSET IBD ........................................................................................16 1.4 IBD THERAPEUTICS ............................................................................................20 1.4.1. Disease burden, complications, personalized treatment ........................................20 1.4.2. The role of CS in IBD ....................................................................................23 1.4.3. Modern treatment paradigms: therapeutic drug monitoring and step up therapy .........26 1.4.4. Therapeutic challenges .................................................................................29 1.5 PHARMACOLOGY OF ABC TRANSPORTERS .......................................................................30 1.5.1. ABCB1 and relevance to IBD susceptibility and response to CS ...............................34 1.5.2. ABCB5 structure and relevance to ABCB1.......................................................... 41 1.5.3. Role of ABCB5 ..............................................................................................44 1.5.4. ABCB5 and multidrug resistance ......................................................................46 1.5.5. ABCB5 and malignancy ..................................................................................49 1.5.3. ABCB5 and potential relevance to IBD ...............................................................51 1.6 AIMS OF THESIS ................................................................................................51 CHAPTER 2 .........................................................................................................54 THE EXPRESSION AND FUNCTION OF THE NOVEL ABC EFFLUX TRANSPORTER ABCB5 ..............54 2.1 INTRODUCTION .................................................................................................55 2.2 MATERIALS AND METHODS .....................................................................................59 2.2.1. Drugs and chemicals ....................................................................................59 2.2.2. Plasmids ...................................................................................................59
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