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2014 Jonathan Alan Hardman Chronobiology of the hair follicle: Dissecting the role of BMAL1 and PER1 in the control of human hair growth and pigmentation A thesis submitted to the University of Manchester for the degree of Doctor of Philosophy In the Faculty of Medical and Human Sciences 2014 Jonathan Alan Hardman School of Medicine The Centre for Dermatology Research, Institute of Inflammation and Repair and the Doctoral Training Centre in Integrative Systems Biology 1 Table of contents Table of figures ..................................................................................................................................9 List of Tables ................................................................................................................................... 12 List of Abbreviations ...................................................................................................................... 13 Abstract ............................................................................................................................................ 15 Declaration ....................................................................................................................................... 16 Copyright statement ....................................................................................................................... 16 Acknowledgements ........................................................................................................................ 17 Chapter 1: Structure and scope of thesis ..................................................................................... 18 Chapter 2: Introduction and literature review ............................................................................. 21 Introduction ..................................................................................................................................... 22 Literature Review .......................................................................................................................... 24 2.1 The human hair follicle ............................................................................................................ 24 2.1.1 Hair follicle anatomy ......................................................................................................... 24 2.1.2 Hair follicle morphogenesis .............................................................................................. 28 2.1.3 The Hair cycle .................................................................................................................. 30 2.2 Chronobiology ......................................................................................................................... 39 2.2.1 Chronobiology in health and disease ............................................................................... 40 2.2.2 The molecular clock ......................................................................................................... 41 2.2.2 Clock genes and the hair follicle. ..................................................................................... 47 2.3 Human melanogenesis and melanocyte biology .................................................................... 49 2.3.1 Introduction ...................................................................................................................... 49 2.3.2 Melanocyte biology .......................................................................................................... 49 2.3.2 Melanogenesis ................................................................................................................. 54 2.3.3 Melanogenesis and the molecular clock .......................................................................... 58 2.3.4 Hair greying ...................................................................................................................... 59 2.4 Hormonal regulation of the hair follicle .................................................................................... 61 2.4.1 Hormones and the circadian clock ................................................................................... 61 2 2.4.2 The HPT axis ................................................................................................................... 64 2.5 Major open questions and aims of thesis ................................................................................ 67 2.6 Experimental design ................................................................................................................ 69 Chapter 3: Material and methods .................................................................................................. 71 3.1 Tissue culture methodologies. ................................................................................................ 72 3.1.1 Tissue collection and ethics ............................................................................................. 73 3.1.2 Hair follicle micro-dissection............................................................................................. 73 3.1.3 Hair follicle organ culture .................................................................................................. 73 3.1.4 Staging hair follicles ......................................................................................................... 74 3.1.5 Hair follicle synchronisation.............................................................................................. 76 3.1.6 Hormone treatment .......................................................................................................... 76 3.1.7 Skin organ culture ............................................................................................................ 76 3.1.8 Human primary epidermal melanocyte culture. ............................................................... 77 3.1.9 Small interfering RNA (siRNA) mediated gene knock-down............................................ 78 3.1.10 Time series experiments ................................................................................................ 79 3.2 Immunohistochemistry and immunofluorescence ................................................................... 80 3.2.1 Tissue processing ............................................................................................................ 80 3.2.2 Sample preparation for high-resolution light microscopy (HRLM) ................................... 80 3.2.3 Immunofluorescence protocols. ....................................................................................... 80 3.2.4 Melanin histochemistry (Masson-Fontana) ...................................................................... 81 3.2.5 PER1/BMAL1 double-immunostaining with cytokeratin 15 (K15). ................................... 81 3.2.5 Ki-67 - TUNEL immunohistochemistry for proliferation and apoptosis ............................ 82 3.2.6 Enzymatic activity for tyrosinase activity. ......................................................................... 83 3.3 Quantitative immunohistomorphometry .................................................................................. 86 3.3.1 PER1 and BMAL1 expression in the human HF. ............................................................. 86 3 3.3.2 Ki-67/TUNEL stain for proliferative and apoptotic cells. .................................................. 87 3.3.3 Assessment of melanin content (Masson-Fontana). ....................................................... 88 3.3.4 Melanosome number. ...................................................................................................... 89 3.3.5 Assessment of immunoreactivity in the HFPU. ................................................................ 89 3.4 Quantitative- real time PCR (qRT-PCR) ............................................................................. 90 3.4.1 Messenger-RNA extraction .............................................................................................. 90 3.4.2 Reverse transcription ....................................................................................................... 90 3.4.3 Quantitative RT-PCR (qRT-PCR) .................................................................................... 91 Chapter 4: A meeting of two chronobiological systems: circadian proteins Period1 and BMAL1 modulate the human hair cycle clock.............................................................................. 94 .......................................................................................................................................................... 94 4.1 Authors .................................................................................................................................... 95 Candidate’s contribution ............................................................................................................ 95 Authors’ contribution ................................................................................................................. 96 4.2 Abstract ................................................................................................................................... 97 4.3 Introduction ............................................................................................................................. 98 4.4 Results .................................................................................................................................. 101 4.4.1 Human anagen HFs transcribe
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