(A*Star Studentship) Age-associated reprogramming of skin mast cell activities

Primary Supervisor (University of Manchester): Professor Silvia Bulfone-Paus

A*Star Supervisor: Professor Anis Larbi

Since mast cells numbers increase in ageing skin, it has been speculated that they may play a major, as yet uncharted role, in skin ageing and ageing-associated skin disease. Mast cells are prototypic “switchboard” cells that are strategically located at host/environment interfaces, such as the skin, where they operate as professional immune sentinels, equipped with a broad repertoire of receptors capable of detecting allergens, infection, and inflammation. They localize in the dermis in close proximity to blood vessels, nerves and skin appendages and undergo activation, degranulation, and cytokine/chemokine secretion while their numbers increase substantially in common inflammatory dermatoses and during skin ageing. Under homeostatic conditions, mast cells are thought to display an immuno-inhibitory phenotype that changes to a disease-promoting, pro-inflammatory phenotype, depending on the local tissue micro-milieu. However, the heterogeneity of human skin mast cells and the plasticity of their phenotypes during skin ageing are poorly understood.

Although the numbers of human skin mast cells gradually increase with age, interestingly, elderly individuals rarely develop new allergies. Therefore, we shall explore the working hypothesis that ageing in murine and human skin is associated with excessive mast cell numbers that display a modified, “non-allergic” phenotype, with altered signalling and/or metabolic activities that specifically promote “inflamm-aging”, possibly via a mast cell “senescence-associated secretory phenotype”. The central objective of this innovative and translationally relevant PhD project is to: a) delineate the effects of ageing on the mast cell molecular signature and effector functions; b) characterise for the first time a potential senescence-associated secretory phenotype (SASP) of human and mouse skin mast cells, and; c) assess whether and how skin mast cells promote skin ageing. Targeting and counteracting undesired skin mast cell activities could become a promising novel anti-ageing strategy with far-reaching clinical implications.

This interdisciplinary project will is guided by the complementary expertise and methodological know-how of a mast cell biologist and an immunosenescence expert, who both focus on mammalian skin as their key ageing model, using instructive state-of-the-art research models, including senescence-accelerated mice (SAMice). Methodologically, the project will include advanced immunofluorescence double-labelling, single cell transcriptomic analysis, deep immunophenotyping and metabolic/proteomic approaches.

This project is to be funded under the University of Manchester-A*STAR PhD Programme. If you are interested in this project, please make direct contact with the Principal Supervisor ([Email Address Removed]) to arrange to discuss the project further as soon as possible. You MUST also submit an online application form, full details on how to apply can be found on the Manchester-A*STAR website http://www.singaporeastar.manchester.ac.uk/

Applications are invited from UK/EU students. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equiv) in a relevant subject area. We may consider applicants from outside of the EU, however there are some restrictions and fee implications, see website for full details before making an application.

http://www.inflammation-repair.manchester.ac.uk/staff/154736

http://www.a-star.edu.sg/sign/Research/Principal-Investigators/tid/11/LARBI-Anis.aspx