The following information can also be found on findaphd.com.
About the Project
Immunosenescence increases susceptibility to infection and through decreased immune surveillance promotes ageing more generally. The ageing immune system also becomes overactive or dysregulated, causing inflammation, an important ageing mechanism. These aspects of the ageing immune system were highlighted by COVID-19, with the elderly and immunocompromised at high risk, and, seemingly in contradiction, patients with overly strong immune reactions at high risk of mortality. To combat ageing, it is crucial to understand which immune components require potentiation and which require suppression during ageing. Progress in understanding the ageing immune system has been hindered by the absence of tools allowing precise manipulation of immune cell subpopulations.
The white blood cells known as macrophages play key roles in development, homeostasis and immunity. Macrophages are highly heterogeneous and this diversity is critical to their ability to perform a wide range of functions in healthy individuals but also relates to their pleiotropic dysfunction in many diseases. We recently identified pro-inflammatory macrophage subpopulations in fruit flies (Drosophila) that change in their abundance during ageing, importantly developing tools to manipulate them precisely. Only when we understand the fundamental biology of ageing immune systems can we develop rejuvenation therapies – we aim to make key progress in this area by combining ageing research with immune biology, key areas of expertise in the Simons and Evans labs, respectively.
Objectives and experimental approach
We hypothesise that, depending on macrophage subpopulation, either decreasing or increasing the numbers of these cells will rejuvenate immunity and deter ageing. Molecular characterisation of subpopulations during ageing will identify candidate mechanisms underlying how immune cells prevent and/or drive ageing. Our model uniquely allows large-scale, in vivo testing of the importance of macrophage subpopulations during ageing. Firstly, we will characterise where these cells localise and how their abundance changes during ageing. Secondly, we will increase and decrease subpopulations to directly test their function during ageing; assays on functional performance (lifespan/fecundity/injury responses/infection) will identify which aspects of physiology are impacted. Thirdly, we will compare transcriptomes of macrophages in young and aged flies to identify candidate mechanisms and test for causality using functional genetics. Importantly, we have already generated the cutting-edge tools to manipulate and visualise subpopulations during ageing.
Training and environment
The successful applicant will receive in-depth training in fly genetics, molecular biology, functional assays, in vivo imaging, image analysis and bioinformatics. These skills are highly transferable and sought after in industry. The student will integrate into two dynamic and welcoming research groups, members of the Bateson Centre and Healthy Lifespan Institute.
Your PhD studies will provide the first proof-of-principle whether enhancing or suppressing the function of specific immune cell populations promotes healthy ageing. Longer term, this work has the potential to identify mechanisms involved in how macrophages contribute to/protect against age-related decline. Such insights will help generate new precise anti-ageing therapies and life-style advice.
Lab websites/Twitter:
https://www.sheffield.ac.uk/biosciences/people/academic-staff/mirre-simons
https://simons-lab.group.shef.ac.uk/
https://www.sheffield.ac.uk/medicine/people/iicd/iwan-robert-evans
http://iwanrevans.weebly.com/
@mirresimons
@delaevanio
Please do not hesitate to get in contact to discuss this project in the first instance.
Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme and how to apply can be found on our website:
http://www.dimen.org.uk/how-to-apply/application-overview
Funding Notes
Studentships are fully funded by the Medical Research Council (MRC) for 4yrs. Funding will cover UK tuition fees, stipend and project costs as standard. We also aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will be awarded to exceptional candidates only, due to the competitive nature of this scheme. Please read additional guidance here: View Website
Studentships commence: 1st October 2022
Good luck!
References
Coates, J., Brittle, A., Armitage, E., Zeidler, M. & Evans I. Identification of functionally-distinct macrophage subpopulations in Drosophila. eLife 10:e58686 (2021). https://elifesciences.org/articles/58686
McCracken, A., Adams, G., Hartshorne, L., Tatar, M. & Simons, M. The hidden costs of dietary restriction: Implications for its evolutionary and mechanistic origins. Sci. Adv. 6: eaay3047 (2020). https://www.science.org/doi/10.1126/sciadv.aay3047
Min, K-J & Tatar, M. Unraveling the Molecular Mechanism of Immunosenescence in Drosophila. Int. J. Mol. Sci. 19:2472 (2018). https://www.mdpi.com/1422-0067/19/9/2472
Mase, A., Augsburger, J. & Brückner, K. Macrophages and Their Organ Locations Shape Each Other in Development and Homeostasis - A Drosophila Perspective. Front. Cell Dev. Biol. 9:630272. https://www.frontiersin.org/articles/10.3389/fcell.2021.630272/full