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    The role of miRNA-486-5p in hair growth and the hair follicle immune privilege. Role of miRNAs in alopecia areata

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    PhD Thesis (13.86Mb)
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    Publication date
    2020
    Author
    Broadley, David P.
    Supervisor
    Botchkareva, Natalia V.
    Mardaryev, Andrei N.
    Keyword
    Alopecia areata
    Hair cycle
    Hair follicle
    Immune privilege
    MicroRNA
    Rights
    Creative Commons License
    The University of Bradford theses are licenced under a Creative Commons Licence.
    Institution
    University of Bradford
    Department
    Centre for Skin Sciences, Faculty of Life Sciences
    Awarded
    2020
    
    Metadata
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    Abstract
    MiRNAs control skin homeostasis through post-transcriptional gene repression by binding to their target mRNAs. However, their role in regulation of apoptosis and hair loss in alopecia areata (AA) is largely unknown, which became the aim of this study. In AA mouse model (C3H/HeJ), global miRNA profiling revealed 22 miRNAs with significant changes in their expression in AA affected skin. Amongst these miRNAs, miR-486-5p was dramatically decreased in alopecic skin in both humans and mice, in striking contrast to its prominent expression in the hair follicle (HF) epithelium of healthy anagen skin. Moreover, the expression of both pri-miR-486 and miR-486 is down-regulated in the human anagen HFs and keratinocytes treated with IFN-g, one of the key factors contributing to the immune privilege (IP) collapse in HFs. Intradermal delivery of miR-486-5p mimic into mouse skin affected by AA prevented premature entrance of HFs into catagen phase and reduced the numbers of CD4+ and CD8+ lymphocytes in the peri- and intra-follicular skin compartments. Consistently, subcutaneous administration of miR-486-5p inhibitor delayed anagen progression associated with a higher number of intrafollicular NKG2D+ cells in C3H/HeJ mice. Silencing of miR-486-5p in human anagen HFs ex vivo caused premature catagen development and led to suppression of IP by up-regulating HLA class 1, IRF1, ICAM1 and CADM1 expression of which CADM1 was confirmed to be a direct target of miR-486- 5p. Transcriptome profiling of primary human epidermal keratinocytes overexpressing miR-486-5p revealed damping the signalling pathways associated with inflammatory chemokines, cytokines and interleukins. Taken together, these data suggest that miR-486-5p plays a protective role in the pathogenesis of AA by maintaining anagen phase and preventing the IP collapse.
    URI
    http://hdl.handle.net/10454/19059
    Type
    Thesis
    Qualification name
    PhD
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    Theses

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