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The EV-glycome: the coming of age of a novel biomarker?


Project Description

Cellular senescence is the permanent loss of a cell’s ability to divide. Although no longer dividing, senescent cells remain metabolically active and develop a secretory, inflammatory phenotype termed the SASP.

In the body, increased cellular senescence is associated with several age-related pathologies including neurodegenerative disease, impaired wound healing, and cancer. Several recent studies have demonstrated the ability of drugs that selectively target senescent cells (senotherapeutics) to reduce age-related disease severity and increase healthy lifespan in laboratory animals. Thus, there is considerable and growing interest in the utility of senotherapeutics to increase healthy lifespans in humans.

One major difficulty impeding development of senotherapeutics for clinical use is a lack of in vivo biomarkers of senescence to monitor drug responses. At present, the only options available for minimally-invasive monitoring of senescence is analysis of circulating levels of constituents of the SASP (for example IL6, CCL2), but these are also elevated in a variety of inflammatory conditions making them poor biomarkers of senescence. Recent evidence suggests that the levels of specific glycans (sugars) are altered on the surface of senescent cells, identifying a novel source of senescence-specific biomarkers.

Very recently, our group has shown that senescent cells release membrane-bound vesicles termed extracellular vesicles (EV). The cargo of EV reflects the constituents of the parent cell, including the glycome. They are found in all body fluids, are readily detectable and stable, making them ideal source of biomarkers. In addition, EV play a number of functional roles in health and disease by acting as messengers between cells.

The aim of this project is to test the hypothesis that the EV glycome plays a role in the function of senescent cells and represents an ideal biomarker for monitoring senescence, and by extension biological age and related pathologies.

The project will address key research questions:

1. Does the EV-glycome differ between proliferating and senescent oral cells?
2. Does depletion of senescent cells using senotherapeutics in 2D and 3D in vitro models alter the EV-glycome?
3. Does depleting glycans from senescent cell-derived EVs affect function?

This project is a collaboration with Ludger Limited, a world leader in glycoanalytical technology with a business interest in glycan-based health monitoring and biomarker development. It will increase understanding of the nature and function of the EV glycome and pave the way for development of potentially novel biomarkers of ageing and facilitate the translation of a new wave of therapies targeting age-related morbidity.

Funding Notes

Funding:
These studentships will be 42 months in duration, and include home fee and stipend at UKRI rate.

Eligibility:
Candidates must have a first or upper second class honors degree or significant research experience.

References

Enquiries:
Interested candidates should in the first instance contact Dr Dan Lambert ([email protected])

How to apply:
Please complete a University Postgraduate Research Application form available here: www.shef.ac.uk/postgraduate/research/apply

Please clearly state the prospective main supervisor in the respective box and select 'Neuroscience' as the department.

Deadline for applications is 5pm on Wednesday 29th January 2020. Late applications will not be accepted. Interviews are scheduled to be held on Tuesday 25th February 2020.

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