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Hair follicle dysbiosis and immune privilege alteration as drivers of human skin dysfunction, interrogating dandruff pathogenesis as a model


Project Description

Despite the psycho-social burden of dandruff and the commercial relevance of its management, the molecular and cellular pathobiology of this condition is poorly understood. Indeed, Dandruff is now considered to represent a multifactorial condition characterised by keratinocyte hyperproliferation and abnormal terminal differentiation paired with excessive immune cell infiltration (1) caused in part by excessive microbial colonisation (dysbiosis).

The HF is one of the few immune-privileged (IP) organs of the human body, allowing it to be relatively ignored by the immune system (2,3) under physiological circumstances. To maintain its immunoinhibitory microenvironment the HF actively suppresses inflammation and promotes immune tolerance by expressing low levels of MHC-class I and “danger” signals like MICA and high levels of immunoinhibitory proteins e.g. alpha-MSH, TGF-beta-1/2 as well as the “no danger” signal, CD200 (2–5). The loss of any of these mechanisms promotes IP-collapse and can lead to permanent or reversible autoimmune alopecia (e.g. lichen planopilaris, alopecia areata).
As dandruff occurs exclusively in hair-bearing skin and shows perifollicular infiltrates, we hypothesise that a collapse of the hair follicle’s (HF) immune privilege (IP) plays a key role in dandruff pathogenesis. We postulate that HF dysbiosis, the excessive secretion/expression of chemokines and other “danger” signals, and the insufficient production of anti-inflammatory “IP guardians” (alpha-MSH and TGF-beta-1/2) play an important role in dandruff pathogenesis that mandates targeting by more effective and longer-lasting future anti-dandruff therapies.


The successful candidate will learn human human skin organ culture techniques (6), become expert in immunohistology, quantitative immunohistomorphometry, laser capture microdissection, Luminex technology, RNA-sequencing, professional data mining of gene and protein expression profiles (7,8). Within the lab environment candidates will be encouraged to publish there work and develop as a scientist with support from Unilever, leading industry professionals.


Entry Requirements
Applicants are expected to hold, or about to obtain, a minimum upper second class undergraduate degree (or equivalent) in a biological science. A Masters degree in a relevant subject and/or experience in a research setting is desirable.

Funding Notes

BBSRC iCASE Award with Unilever. Studentship funding is for a duration of four years and covers UK/EU tuition fees and an annual minimum stipend of £18777 per annum (2019/20). On the online application form select PhD Dermatological Sciences.

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

1. Kerr, K. et al. Epidermal changes associated with symptomatic resolution of dandruff: Biomarkers of scalp health. Int. J. Dermatol. 50, 102–113 (2011).

2. Paus, R., Bulfone-Paus, S. & Bertolini, M. Hair Follicle Immune Privilege Revisited: The Key to Alopecia Areata Management. J. Investig. Dermatology Symp. Proc. 19, S12–S17 (2018).

3. Ito, T. et al. Collapse and restoration of MHC class-I-dependent immune privilege: exploiting the human hair follicle as a model. Am. J. Pathol. 164, 623–34 (2004).

4. Paus, R., Nickoloff, B. J. & Ito, T. A ‘hairy’ privilege. Trends Immunol. 26, 32–40 (2005).

5. Meyer, K. C. et al. Evidence that the bulge region is a site of relative immune privilege in human hair follicles. Br. J. Dermatol. 159, 1077–1085 (2008).

6. Langan, E.A. et al. Human hair follicle organ culture: theory, application and perspectives. Exp Dermatol. 24(12):903-11.

7. Hawkshaw, N.J. et al. Identifying novel strategies for treating human hair loss disorders: Cyclosporine A suppresses the Wnt inhibitor, SFRP1, in the dermal papilla of human scalp hair follicles. PLoS Biol. 8;16(5):e2003705 (2018).

8. Cheret, J. et al. Olfactory receptor OR2AT4 regulates human hair growth. Nat Commun. 18;9(1):3624 (2018).

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