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(A*STAR) Regulatory pathways and skin barrier function


Project Description

Maintaining a healthy skin barrier is vital for our health and in response to skin wounding, we have a well -orchestrated immune response that heals the breach. Delays in wound healing causing non-healing wounds such as diabetic, venous and pressure ulcers affect one in 50 people, impose a substantial burden on global Health Services and lead to significant patient morbidity and mortality. The process of wound healing is a highly orchestrated process involving many cell types and regulatory networks. Crucially, the outermost cell layer of the skin, the keratinocytes must migrate and proliferate in order to help seal the wound. Chronic non-healing wounds are characterized by a failure of the wound edge keratinocytes to migrate, preventing the wound from healing. Our work has shown that Arginase (ARG1) and the downstream polyamines and polyamine regulators such as AMD1 are crucial factors in the normal wound healing response by promoting keratinocyte migration and proliferation. ARG1 and the polyamines also influence macrophage and anti-microbial functions. ARG1 is significantly down regulated in elderly patients with non-healing wounds suggesting this is a crucial regulator of the barrier response. Notably, alteration in the keratinocyte migratory and proliferative response are also associated with a host of skin conditions such as psoriasis emphasising the importance of regulating the barrier response for our health.

This project addresses the role of the Arginase pathway and its downstream metabolites, polyamines, in the regulation of skin barrier formation and the epidermal inflammatory response during wound healing. The project will use combination of human cell culture and human tissue analysis combined with genome wide RNA sequencing studies to interrogate the interplay between the polyamine pathway, the inflammatory response and keratinocyte behaviour in the epidermis. Students on the project will develop expertise in immunology biochemistry and cell biology. These studies are aimed at understanding the regulatory controls governing normal epidermal cells with the aim of better understanding clinical epidermal conditions such as delayed wound healing.

Entry Requirements:
Applications should be submitted online and candidates should make direct contact with the Manchester supervisor to discuss their application directly. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is available to UK/EU candidates. Funding covers fees (UK/EU rate) and stipend for four years. Overseas candidates can apply providing they can pay the difference in fees and are from an eligible country. Candidates will be required to split their time between Manchester and Singapore, as outlined on View Website.

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

Kheng LH, Rahim AB, Leo VI, Shatarupa D, Lim TC, Uemura T, Igarashi K, Common J,Vardy LA. (2018) Polyamine regulator AMD1 promotes cell migration in epidermal wound healing., J Invest Dermatol. 2018 Jun 12

James C, Zhao TY, Muthalif N, Uemura T, Tsuneyoshi N, Ong S, Igarashi K, Lim CY, Dunn NR, Vardy LA (2018) MINDY1 is a downstream target of the polyamines and promotes embryonic stem cell self-renewal, Stem Cells. 2018 Apr 12.

Williams H, Crompton RC, Thomason HA, Laura Campbell L, Gurdeep Singh G, McBain AJ, Cruickshank SM, Hardman MJ Cutaneous Nod2 expression regulates the skin microbiome and wound healing in a murine model J Invest Dermatol 137(11), 2427-2436 (2017)

Campbell L, Saville C, Kitagawa Y, Murray PJ, Cruickshank SM, M Hardman. Dermal arginase 1 impairs cutaneous healing with an altered inflammatory response. J Invest Dermatol 2013 133: 2461–2470

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