BBSRC NLD Doctoral Training Partnership: Understanding and enhancing nuclear dynamics for microglial replacement therapy


   Faculty of Medical Sciences

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  Dr Michael J Keogh, Prof Matthew Collin, Dr I Karakesisoglou  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

Microglia are the major immune cell of the brain playing a critical role the progression of age-related disorders such as Alzheimer’s disease (AD). Studies in mice suggest that microglia develop in early life and are a self-renewing population of cells that are not added to by immune cells from the blood (such as monocytes) crossing into brain. Recently however it has been determined that some monocytes in the blood of aging humans do cross into the brain and convert into microglia, meaning that new microglia are added to by monocytes from blood. These monocytes however carry a mutation called a CHIP-mutation, which importantly, are associated with reducing the risk of AD.

At present we don’t understand what allows some monocytes such as those carrying CHIP-mutations to cross into brain, migrate across brain, and turn into miroglia. This is important to understand in order to harness these mechanisms to develop further treatments for AD and potentially many other disorders.

One critical factor determining the ability of a cell to invade a tissue is the cell nucleus. As the biggest part of the cell it can often block cellular movement due to its size and stiffness as it tries to ‘squeeze’ through gaps in tissues. Whilst cells do have a mechanism to distort the nucleus called the LINC complex, the role of this complex in either healthy immune cells such as monocytes, or in the context of immune cells carrying CHIP mutations has not been fully determined.

In this proposal you will work with an academic neurologist, haematologist and leader in the field of nuclear cell dynamics to differentiate monocytes from patient and control bone marrow and determine whether healthy or CHIP-mutant monocytes migrate differently through a variety of extra-cellular matrixes. You will use microscopy and quantitative imaging analyses to detect changes in the nucleus that occur dynamically, and perform immunohistochemistry to determine this. Secondly, you will use siRNAs to knock-down key mediators of nuclear movement to see if you can enhance monocyte movement into and across the brain, potentially identifying new therapeutic approaches that can be developed to enhance cell entry and migration into brain.

We believe this project is a wonderful opportunity for a transdisciplinary project that could lead to an understanding of the protective effect of CHIP-mutant monocytes and understand how we can develop new regenerative cellular therapies for age-related neurological disease.

HOW TO APPLY:

Applications should be made by emailing [Email Address Removed] with:

  • a CV (including contact details of at least two academic (or other relevant) referees);
  • a covering letter – clearly stating your first-choice project, and optionally 2nd ranked project, as well as including whatever additional information you feel is pertinent to your application; you may wish to indicate, for example, why you are particularly interested in the selected project(s) and at the selected University;
  • copies of your relevant undergraduate degree transcripts and certificates;
  • a copy of your IELTS or TOEFL English language certificate (where required);
  • a copy of your passport (photo page).

A GUIDE TO THE FORMAT REQUIRED FOR THE APPLICATION DOCUMENTS IS AVAILABLE AT https://www.nld-dtp.org.uk/how-apply. Applications not meeting these criteria may be rejected.

In addition to the above items, please email a completed copy of the Additional Details Form (as a Word document) to [Email Address Removed]. A blank copy of this form can be found at: https://www.nld-dtp.org.uk/how-apply.

Informal enquiries may be made to [Email Address Removed] 

The deadline for all applications is 12noon on Monday 15th January 2024.

 

Part-Time Study Options

All NLD DTP PhDs are available as part time or full time, with part time being a minimum of 50% of full time. Please discuss potential part time arrangements with the primary supervisor before applying to the programme.

Project CASE Status

This project is not a CASE project. While individual applicant quality is our overriding criterion for selection, the NLD DTP has a commitment to fund 8 CASE projects per year - as such, CASE projects may be favoured in shortlisting applicants when candidates are otherwise deemed to be equal or a consensus on student quality cannot be reached. 

Biological Sciences (4) Medicine (26)

Funding Notes

BBSRC NLD DTP programme – starting October 2024.
UKRI provide the following funding for 4 years:
• Stipend (2023/24 UKRI rate £18,622)
• Tuition Fees at UK fee rate (2023/24 rate £4,712)
• Research support and training grant (RTSG)
Note - UKRI funding only covers UK (Home) fees. The DTP partners have various schemes which allow international students to join the DTP but only be required to pay home fees. Home fees are already covered in the UKRI funding, meaning that successful international candidates do not need to find any additional funding for fees.

References

1. High prevalence of focal and multi-focal somatic variants in the human brain. Nature Communications. 9. 4257 (2018). (IF 16.6).
2. Frequency and signature of somatic variants in 1461 human brain exomes. Genetics in medicine. 21, 904–912 (2019). (IF 8.9).
3. Donor monocyte-derived macrophages promote human acute graft-versus-host disease. J Clin Invest. 2020;130:4574-4586. (IF 15.9).
4. Nesprin interchain associations control nuclear size. Cell. Mol. Life Sci. 69, 3493-3509. (2012) (IF 9.2)
5. Cytotoxic T lymphocyte effector function is independent of nucleus-centrosome dissociation. Eur. J. Immunol. 42, 2132-2141. (2012) (IF 6.7)