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  MSc By Research: Using hypomethylating agents to prevent respiratory infections in older adults


   School of Medicine, Medical Sciences & Nutrition

  ,  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

The MSc by Research programme at the University of Aberdeen is for students interested in a research-intensive master's degree. It is designed specifically to enhance your skills for a PhD or research career. If you have your own ideas for a research project in this area, we would love to hear from you! Please reach out to one of the project supervisors above to discuss your ideas.

You can find further information about our academic requirements and programme structure here.

Background: Older adults (50+ years) are at increased risk for severe respiratory infections. The increased susceptibility has generally been attributed to age-related remodelling of the immune system termed immunosenescence. Recent evidence indicates that this immune remodelling may be due to acquired mutations in epigenetic regulators that result in DNA ‘hypermethylation’ in promotor regions, repressing genes involved in proper haematopoiesis. This DNA hypermethylation has become a hallmark of ageing and is considered one of the major mechanisms of age-associated monocyte dysfunction.

One drug candidate that has been shown to reverse DNA hypermethylation is 5-azacytidine (AZA), a hypomethylating agent (HMA). Recent investigations have identified potential direct effects of hypomethylating agents on immune cell subsets. However, the use of HMAs to reduce infectious disease risk in older adults has yet to be explored, providing an exciting new avenue for therapeutic intervention. I hypothesize that AZA treatment will improve outcomes of respiratory infections in older adults. The proposed central mechanism of action of HMAs is the reversal of aberrant methylation with ageing, thus reactivating promotors and leading to (re)expression of genes important for proper immune cell differentiation and function. Using ageing mouse models, we will test this hypothesis via the following specific aims:

Aim 1. Determine whether AZA treatment can reverse immunosenescence. To determine if AZA counteracts age-associated immune remodelling, bone marrow samples were collected from mice following AZA treatment. Measurements of immune remodelling will be performed in the frozen bone marrow samples using flow cytometry. Hallmarks of immune ageing, such as TNF and IL-6 will also be measured using qPCR. I predict that mice administered AZA will have reduced monocyte numbers and inflammatory mediators and we will confirm that there are functional benefits by performing bacterial binding and killing assays.

Aim 2. Determine if AZA improves outcomes of respiratory infections. Mice were treated with AZA as in Aim 1. Following treatment (day 6) mice were intranasally inoculated with Streptococcus pneumoniae. At peak infection, lung tissues were harvested. Using these tissues, we will examine microscopic and macroscopic differences in lung pathology and immune cell infiltration. I hypothesize that AZA treatment will reduce inflammatory monocyte infiltration and lung pathology that results in respiratory failure.

Feasibility: All protocols are standard in my laboratory and the tissues have been pre-collected allowing for feasibility.

Summary: The need for discovering new therapies to reduce the risk of respiratory infections in older adults has never been greater. By evaluating the effects of AZA on immune reprogramming and infectious outcomes, I hope to discover an effective therapeutic option for improving the health and survival of older people threatened by respiratory infections.

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Applicants to this project should hold a minimum of a 2:1 UK Honours degree (or international equivalent) in a relevant subject.

We encourage applications from all backgrounds and communities, and are committed to having a diverse, inclusive team.

Informal enquiries are encouraged, please contact Dr Candice Quin () for further information.

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APPLICATION PROCEDURE:

Please note: This is a self-funded opportunity.

  • Prospective students should contact the lead supervisor (via the email address listed above) to discuss the research project and complete a proposal form prior to / or shortly after applying.
  • Formal applications can be completed online: https://www.abdn.ac.uk/pgap/login.php
  • You should apply for Medical Sciences (MSc) to ensure your application is passed to the correct team.
  • Please clearly note the name of the supervisor and the project title on the application form. If this is not included, your application may not be considered for the project.
  • Candidates should have (or expect to achieve) a minimum of a 2:1 UK Honours degree (or international equivalent) at undergraduate level.
  • Your application must include: a personal statement, an up-to-date copy of your academic CV, and clear copies of your educational certificates and transcripts.
  • If you are still undertaking your undergraduate degree, it is helpful to the selection panel if you could provide documentation showing your grades to date (this can be a screenshot from an online portal).
  • Please note: Project supervisors will not respond to requests for funding assistance.
  • If you require any additional assistance in submitting your application or have any queries about the application process, please don't hesitate to contact us at 
Biological Sciences (4) Medicine (26)

Funding Notes

This is a self-funding project open to students worldwide. Our typical start dates for this programme are February or October.
Fees for this programme are £4,712 for home/UK students, and £24,860 for international students.
Additional research costs / Bench fees of £3,000 will also apply.
The Scottish Government offers postgraduate loans to those due to start a Masters (taught or research) programme.

References

1. Fulop T, Larbi A, Dupuis G, Le Page A, Frost EH, Cohen AA, et al. Immunosenescence and Inflamm-Aging As Two Sides of the Same Coin: Friends or Foes? Front Immunol. 2017;8:1960.
2. Ferrone CK, Blydt-Hansen M, Rauh MJ. Age-Associated TET2 Mutations: Common Drivers of Myeloid Dysfunction, Cancer and Cardiovascular Disease. Int J Mol Sci. 2020;21(2).
3. Lindblad KE, Goswami M, Hourigan CS, Oetjen KA. Immunological effects of hypomethylating agents. Expert Rev Hematol. 2017;10(8):745-52.

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