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  Defining the mechanism of skin barrier restoration by bacterial lysates


   London Interdisciplinary Biosciences Consortium (LIDo)

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  Dr R O'Shaughnessy, Dr C O'Neill, Dr D Bergamaschi  No more applications being accepted  Funded PhD Project (Students Worldwide)

About the Project

To apply for this project please visit the LIDo website: https://www.lido-dtp.ac.uk/apply

The outer layer of the skin, the epidermis, is the main barrier to the environment: post-mitotic cells terminally differentiate to form a tough outer cornified layer of anucleate flattened cells that confer the majority of skin barrier function. The O’Shaughnessy Lab has a particular interest in the molecular mechanisms related to skin barrier function, and the industrial supervisor, Professor Catherine O’Neill studies the effect of probiotic bacteria on skin barrier function. SkinBioTherapeutics have developed a topical formulation containing bacterial lysates. We wish to understand mechanistically how bacterial lysates induce their skin barrier enhancing effects. We hypothesise that these lysates enhance skin barrier through several different mechanisms, some of which are described in the references below.

The student will test microbial lysates and fractions thereof developed by SkinBioTherapeutics in barrier deficient and competent keratinocytes and 3D skin-equivalent organotypic cultures to understand how they restore or enhance skin barrier. The student will perform proteomics to identify biomarkers of efficacy of the microbial lysates. This work will be critical to identify downstream actives within the microbial preparations, and important to skin barrier biology research by improving understanding not only of skin barrier function, but also bacteria-host interaction, currently a “hot-topic” in skin biology research.

Objectives:

1. Testing the ability of bacterial lysates to rescue physical and immune skin barrier function

2. Determining the proteomic profile of keratinocytes treated with bacterial lysates to identify pathways and biomarkers associated with barrier enhancement

3. Fractionation of lysates and assaying biomarkers to identify key actives within the bacterial lysates.

This project combines cell biology, biochemistry, proteomics/bioinformatics and microbiology. This project includes two three-month industrial placements with SkinBioTherapeutics in years 2 and 3 of the PhD, where the student will be trained in how to grow bacteria, produce and fractionate bacteria-free lysate products, and identify protein actives.

The student will be primarily based in the Centre for Cell Biology and Cutaneous Research in the Blizard Institute, a highly collaborative environment of 60 researchers working on keratinocyte and epithelial biology, comprising 15 research-active academics and 23 PhD students, where there are frequent beneficial interactions between PhD students and Senior staff. Key strengths include development of skin three-dimensional models, cancer biology and genetics, extracellular matrix biology, epithelial signalling and gene discovery in genetic skin and related diseases, and a particular focus on skin barrier function in health and disease.

To apply for this project please visit the LIDo website: https://www.lido-dtp.ac.uk/apply


Biological Sciences (4) Physics (29)

Funding Notes

Fully funded place including home (UK) tuition fees and a tax-free stipend in the region of £17,609.
LIDo has a maximum of 11 fully funded opportunities for students eligible for overseas fees.

References

-Rogerson C, Wotherspoon DJ, Button R, O’Shaughnessy RFL. Akt-1 associated actomyosin remodeling is required for nuclear lamin dispersal and nuclear shrinkage in epidermal terminal differentiation. Cell Death Differ 2021 Jun;28(6):1849-1864.
- Naeem A, Tommasi C, Cole C, Brown S, Zhu Y, Moffatt M, Cookson B, Harper JI, Di WL, Reinheckel T, Brown S, O’Shaughnessy RFL. A mechanistic target of rapamycin complex 1/2 (mTORC1)/V-Akt murine thymoma viral oncogene homolog 1 (AKT1)/cathepsin H axis controls filaggrin expression and processing in skin, a novel mechanism for skin barrier disruption in patients with atopic dermatitis. Journal of Allergy and Clinical immunology 2017 Apr;139(4):1228-1241
- Akinduro O, Sully K, Chikh A, Robinson DJ, Patel A, McPhail G, Braun K, Philpott MP, Harwood CA, Carolyn Byrne, O'Shaughnessy RFL & Bergamaschi D (Joint Senior Author). Constitutive autophagy and nucleophagy during epidermal development. J Invest Dermatol. 2016 Jul;136(7):1460-70
- Naeem AS, Zhu Y, Di WL, Marmiroli S, O'Shaughnessy RFL. AKT1-mediated Lamin A/C degradation is required for nuclear degradation and normal epidermal terminal differentiation. Cell Death Differ. 2015 Dec;22(12):2123-32
-El chami Foster, AR, Johnson C, Clausen RP, Cornwell, P, Haslam, I, Steward I, Watson REB and O’Neill CA (2021) Organic osmolytes increase expression of specific tight junction proteins in skin and alter barrier function in keratinocytes . Br J Dermatol 184 (3):482-494
-Spacova I, O’Neill CA and Lebeer S (2020) Lacticaiseibacilus rhamnosus GG inhibits infection of keratinocytes by S. aureus. Beneficial Microbes 11(7) 703-715