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Determining the role and mechanism of spatially restricted basement membrane remodelling in regulating mesenchymal-epithelial interactions in skin and limbal stem cell niches


Project Description

This PhD studentship relates to the regulation of epithelial stem cells. The project is a highly exciting discovery science project investigating a series of fundamental questions relating to how the environment in which stem cells reside, the stem cell niche, are formed and modified, and how the cells that assemble the niche interact.

Our work will focus on two key epithelial stem cell niches; the corneal-limbal and hair follicle bulge regions. These two regions are critical in maintaining the cornea and skin respectively in normal situations and during wound repair, while defects in these areas lead to severe clinical disease. Importantly, these two areas are accessible for study of developmental processes in adult organisms and therefore represent extremely elegant self-contained systems for investigation into fundamental biological questions with wide-ranging implications.

In exciting, seminal work from our team, we have identified that the epithelial and stromal cells within these niches interact with one another in specific regions. Specifically, our data have demonstrated that interactions between epithelial and stromal stem cells involve disruption of a structure termed a basement membrane, which usually acts as a barrier between these cells and that these interactions are essential to the function of the stem cells. However, it is not yet known what mechanisms allow this cross-talk to occur. The goal of this studentship is to understand how and why these interactions occur. To do so, we will test a series of hypotheses where we predict the composition of the contact point will reflect its function and that a relatively unstudied family of proteins are directly involved in regulating these interactions.

The supervisory team for this project brings together experts in limbal and hair follicle stem cells, and in basement membrane assembly to generate a custom-designed training platform-specific for this project. Your studentship will involve supervision from researchers at the University of Liverpool and Durham University, and you will spend time in both institutions to conduct specific parts of the project and to learn project-relevant skills.

The project will employ a range of exciting, cutting-edge techniques. These will include but are not limited to advanced imaging approaches including super-resolution microscopy and advanced forms of electron microscopy, as well as 3D cell culture models. Skills in these areas have wide transferability to other research situations and are in high demand. The training you will receive will provide a strong base for your onward research careers

HOW TO APPLY

Applications should be made by emailing with a CV (including contact details of at least two academic (or other relevant) referees), and a covering letter – clearly stating your first choice project, and optionally 2nd and 3rd ranked projects, as well as including whatever additional information you feel is pertinent to your application; you may wish to indicate, for example, why you are particularly interested in the selected project(s) and at the selected University. Applications not meeting these criteria will be rejected.
In addition to the CV and covering letter, please email a completed copy of the Additional Details Form (Word document) to . A blank copy of this form can be found at: https://www.nld-dtp.org.uk/how-apply.
Informal enquiries may be made to

Funding Notes

This is a 4 year BBSRC studentship under the Newcastle-Liverpool-Durham DTP. The successful applicant will receive research costs, tuition fees and stipend (£15,009 for 2019-20). The PhD will start in October 2020. Applicants should have, or be expecting to receive, a 2.1 Hons degree (or equivalent) in a relevant subject. EU candidates must have been resident in the UK for 3 years in order to receive full support. Please note, there are 2 stages to the application process.

References

Tissue engineering of human hair follicles using a biomimetic developmental approach. Nature Communications 2018. 9(1): 5301

Localisation of epithelial cells capable of holoclone formation in vitro and direct interaction with stromal cells in the native human limbal crypt. PLoS One 2014, 9(4): e94283

Microenvironmental reprogramming by three-dimensional culture enables dermal papilla cells to induce de novo human hair-follicle growth. Proceedings of the National Academy of Sciences of the USA 2013., 110(49): 19679–19688

LaNt alpha31 modulates LM332 organisation during matrix deposition leading to cell-matrix adhesion and migration defects. BioRxiV (preprint) 2019

Differential distribution of LaNt alpha31 across the ocular surface; implications for corneal wound repair. Investigative Ophthalmology and Vision Science 2018 Aug 1;59(10):4082-4093

Identification of a novel family of laminin N-terminal alternate splice isoforms: structural and functional characterization. Journal of Biological Chemistry 2009; 284, 35588-96

Recreating the human limbal epithelial stem cell niche with bioengineered limbal crypts. Curr Eye Res. 2016 4:1-8

Response of human limbal epithelial cells to wounding on 3D RAFT tissue equivalents: effect of airlifting and human limbal fibroblasts. Eye Eye Res. 2014 127;196-205

Multifaceted role of hair follicle dermal cells in bioengineered skins. Br J Dermatol. (2017) 176(5):1259-1269

Fluorescently tagged laminin subunits facilitate analyses of the properties, assembly and processing of laminins in live and fixed lung epithelial cells and keratinocytes. (2008) Matrix Biology Sep; 27(7): 640–647

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