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Glucocorticoid Metabolism and Function in Ageing Skin

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Glucocorticoid Metabolism and Function in Ageing Skin Glucocorticoid Metabolism and Function in Ageing Skin By Ana Tiganescu A thesis presented to the College of Medical and Dental Sciences at the University of Birmingham for the Degree of Doctor of Philosophy Centre for Endocrinology, Diabetes and Metabolism, School of Clinical and Experimental Medicine September 2011 University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. SUMMARY The continuing demographic shift towards a greater proportion of elderly individuals in the populations of developing nations and associated increased morbidity is fuelling the drive for increased research into healthy lifespan. Excessive circulating glucocorticoid (GC) levels (e.g. Cushing’s Syndrome) often cause hypertension, osteoporosis, central obesity, muscle weakness, skin thinning and poor wound healing - conditions also commonly associated with the ageing process. Studies in our group investigating the enzyme 11-beta hydroxysteroid dehydrogenase type 1 (11β-HSD1), that generates active GC and regulates their local tissue- specific concentrations, have previously demonstrated increased levels in bone cells derived from older compared to younger donors. This thesis provides exciting new research that reproduces this observation in the organ most noticeably affected by ageing - skin. 11β-HSD oxoreductase activity (i.e. GC-activating) was found to be elevated in skin from older compared to younger donors - with increased enzyme levels in dermal fibroblasts (cells crucial to collagen production and skin remodelling). Activity also was inducible by GC exclusively in cells from older individuals, further increasing dermal cortisol generation potential with advancing age. Evidence is presented for 11β-HSD1- specific regulation of GC target genes in dermal fibroblasts that may be dysregulated during ageing and for novel GC targets in skin that also correlate with enzyme activity. Finally, initial studies characterizing the phenotype of the ageing 11β-HSD1-null mouse reveal exciting morphological alterations in skin structure that are more similar to those of young animals than aged controls. GC are often used to treat a wide range of common skin disorders in the elderly including xerosis (dry skin), bullous pemphigoid (blistering) and psoriasis. However, elderly patients also have an increased risk of developing treatment side-effects including skin thinning, susceptibility to bruising and tearing and increased infection risk. In addition to gaining knowledge of a potential contributor to the skin ageing process, the findings presented in this thesis provide support for development of a novel therapeutic target that may minimize side-effects associated with GC therapy in the elderly and may reduce the ageing process in skin and its associated adverse pathologies. For Dr Sanda Jacomin ACKNOWLEDGEMENTS I would like to express my thanks to Dr Elizabeth Walker and Dr Andrew Mayes for their guidance, encouragement and for being super supervisors and also to Professor Paul Stewart for his inspiration, support and commitment to this research. I would like to thank my collaborators at Unilever Discover; the late Professor William Parish for sharing his time and histological expertise, Dr Nicola Carpenter for her contribution to the immunohistochemistry studies, Dr Mike Saxby for Nuance software assistance, Dr Tony Dadd for statistical advice and Dr Fei Ling for his time and help with Fluidigm Biomark. My gratitude to Dr Aurora Alonso for her assistance with ethics application and particularly to Dr Abd Tahrani for his enthusiasm, advice and help with the biopsy study. To the nurses at the CRF (Theresa Brady and Sarah Borrows), professor Janet Lord for help with recruitment and to all the volunteers who made this research possible. Thanks to my colleagues and friends who I have met over the past four years on the IBR 2nd Floor and have made my PhD an enjoyable and fun experience (particularly to all who also gave me their skin!!). Special thanks to Rowan Hardy (lab-mate, desk-mate, coffee-mate etc.), Rachel Watkins (best-mate), Robbie (pub-mate), Angie (swim-mate) and to Olly (soulmate!). To everyone else who hasn’t been named – you know who you are! Finally, my biggest thanks to my parents Serban and Cristina and my sister Andrea who have always been a constant support. This work was funded by the BBSRC in association with Unilever Discover. ABBREVIATIONS 11β-HSD(1/2) 11 beta-hydroxysteroid dehydrogenase (type 1/2) 11-DHC 11-dehydrocorticosterone ACTH Adrenocorticotrophic hormone AME Apparent mineralocorticoid excess AMP Antimicrobial peptide AP Activating protein APC Antigen-presenting cell BER Base excision repair CPD Cyclobutane pyrimidine dimers CR Caloric restriction CRF Wellcome Trust Clinical Research Facility CRH Corticotrophin-releasing hormone DBD DNA-binding domain DEJ Dermal-epidermal junction DHEA(S) Dehydroepiandrosterone (sulphate) DSB Double-stranded break ECM Extracellular matrix EDTA Ethylenediaminetetraacetic acid EGF Epidermal growth factor FSH Follicle-stimulating hormone GAG Glycosaminoglycan GM-CSF Granulocyte-macrophage colony-stimulating factor GC Glucocorticoid GH Growth hormone GR Glucocorticoid receptor H6PD Hexose-6-phosphate dehydrogenase HDF Primary human dermal fibroblasts HPA Hypothalamic-pituitary-adrenal HPG Hypothalamic-pituitary-gonadal HRE Hormone response element IGF Insulin-like growth factor IL Interleukin IFN Interferon IRS Inner root sheath LBD Ligand-binding domain LH Luteinizing hormone LXR Liver X receptor LPS Lipopolysaccharide MMP Matrix metalloproteinase MMR Mismatch repair MR Mineralocorticoid receptor mtDNA Mitochondrial DNA NAD Nicotinamide adenine dinucleotide NADP(H) Nicotinamide adenine dinucleotide phosphate (reduced) NBF Neutral buffered formalin NER Nucleotide excision repair NF-κB Nuclear factor kappa-light-chain-enhancer of activated B-cells NHEJ Non-homologous end joining NKT Natural killer T NR Nuclear receptor ORS Outer root sheath PARP Poly-(ADP ribose) polymerase PBS Phosphate buffered saline PE Photo-exposed PP Photo-protected PPAR Peroxisome proliferator-activated receptor PPARGC1A Proliferator-activated receptor gamma coactivator 1-alpha ROS Reactive oxygen species SC Stem cell SIRT Sirtuin T2D Type 2 diabetes TGF Transforming growth factor Th1 Type 1 helper T-cell Th2 Type 2 helper T-cell TIMP Tissue inhibitor of metalloproteinase TNF Tumour necrosis factor UV Ultraviolet VEGF Vascular endothelial growth factor VSMC Vascular smooth muscle cell WT Wild-type TABLE OF CONTENTS CHAPTER 1 GENERAL INTRODUCTION 1 1.1 Skin ............................................................................................................................................ 1 1.1.1 Overview ................................................................................................................................ 1 1.2 Skin structure ........................................................................................................................... 2 1.2.1 Key features ........................................................................................................................... 2 1.2.2 Epidermal compartment ......................................................................................................... 3 1.2.2.1 Keratinocyte differentiation ............................................................................................ 3 1.2.2.2 Melanocytes .................................................................................................................. 5 1.2.2.3 Langerhans' cells ........................................................................................................... 6 1.2.2.4 Merkel cells ................................................................................................................... 7 1.2.3 Pilosebaceous unit ................................................................................................................. 7 1.2.4 Eccrine and apocrine glands .................................................................................................. 9 1.2.5 Dermal compartment ........................................................................................................... 11 1.2.5.1 Extracellular matrix ...................................................................................................... 11 1.2.5.2 Dermal fibroblasts ....................................................................................................... 14 1.3 Dermal vasculature, lymphatics and subcutaneous fat ..................................................... 15 1.4 Stem cells ................................................................................................................................ 16 1.5 Skin function ........................................................................................................................... 17 1.5.1 Barrier function ....................................................................................................................
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