PhD studentship: Using the immune system to cure traumatic brain injury

Closing Date

3 Dec 2019

Salary

Competition funded (UK/European students only).

Project Description

Traumatic brain injury is one of the leading causes of death and disability. Around 20% of traumatic brain injury cases are fatal, with survival leading to the number one cause of life-long disability. The immune system is a major contributor to brain damage during traumatic injury, with the inflammatory response driving local neuronal death. This process is mediated by both mechanical pressure placed upon the brain after swelling, and by inflammatory cytokines and small molecules produced in response to the damage. Potentially, the immune system can be harnessed to prevent and cure the damage caused during traumatic brain injury too.

While most cells of the immune system are inflammatory in nature, having evolved to counter infections, Regulatory T cells (Tregs) are a suppressive immune cell type that has evolved to stop the inflammatory process. These cells are autoreactive in nature, and provide a baseline of immunosuppression that covers most organs in the body.

Recent evidence has suggested that Tregs are not only able to halt inflammation, but they can also actively contribute to the repair of tissues following inflammatory damage. For example, they are able to produce high levels of repair-orientated growth factors, such as TGFbeta and amphiregulin, and they are also able to direct local tissue macrophages into a repair-orientated phenotype.

In the healthy brain, it was once thought that Tregs were not present, however, we have recently identified a tissue-resident population of Tregs in the mouse and human brain. Nevertheless, there are very few Tregs present compared to other tissues around the body, which may be the reason why traumatic brain injury results in pathogenic levels of swelling and inflammation during the acute inflammatory stage.

We have developed a new therapeutic based on our previous work on the control of Treg homeostasis, which is able to modify the apoptosis rate and drive local accumulations of Tregs. When targeted to the brain, our treatment is able to increase the number of Tregs in the brain, providing a local anti-inflammatory environment. In preliminary experiments, providing mice with this therapeutic prior to a traumatic brain injury results in a dramatic reduction in brain damage.

The PhD project will be focused on several main questions:
1) How does brain damage occur during traumatic brain injury? To what extent does the process require the presence of inflammation? Which local cell types are participating in the injury?
2) Can we block brain damage in mice under a therapeutic setting? Here we will test whether giving our therapeutic agent in the hours after traumatic brain injury (i.e., a clinically-relevant setting) is able to reduce and reverse brain damage. We will focus on brain pathology and on behaviour/cognition. If needed we will modify the treatment to make it more suitable to a clinical context
3) Does our treatment to expand brain Tregs prevent brain damage or enhance the repair process?
4) What are the molecular mediators that allow brain Tregs to reduce and reverse brain damage? Is it due to anti-inflammatory cytokines? Interactions with microglia or astrocytes?

The Babraham Institute is a world-leader in fundamental biological research investigating the systems that underpin development and healthy ageing. It is a recognised postgraduate University Partner Institute of the University of Cambridge. Starting October 2020 a number of Studentships will be available leading to a University of Cambridge PhD degree. These studentships can be awarded for up to 3.5 or 4 years. In addition, studentships funded by a range of University of Cambridge funding schemes can be held at the Babraham Institute (see the student pages of our website here - https://www.babraham.ac.uk/vacancies-training/phd-programme) and for specific funding sources for EU and overseas graduate student at Cambridge, please visit here - http://www.graduate.study.cam.ac.uk/finance/funding

Please see our website (http://www.babraham.ac.uk/) and the BBSRC website (https://bbsrc.ukri.org/skills/) for details of eligibility and funding. Non-EU nationals must find funding for academic fees and personal support. In cases where applicants must find their own funding, we will require evidence that the level of funding is at least equal to the standard BBSRC/MRC PhD funding package.

Students will join a thriving scientific community situated on an attractive parkland campus near Cambridge. Our 60 students are all members of Cambridge Colleges and participate fully in University social and academic life - https://www.gradschl.lifesci.cam.ac.uk/

Details of our interactive scientific programmes can be found on the Babraham Institute website - http://www.babraham.ac.uk/.
As a student at the Institute, you will have access to all of our outstanding science facilities (https://www.babraham.ac.uk/science-services), each one providing specialist equipment and expertise to support key research techniques and technologies. In addition to our animal facility, imaging, chemical synthesis and mass spectrometry we are able to offer transgenics services, flow cytometry, lipidomics, next-generation sequencing and a highly specialist team of bioinformaticians. In addition, several of our facilities operate training programmes to help you develop your own skills in these key research areas. The Institute’s research groups also incorporate a selection of other cutting-edge specialties including single-cell and multiomics approaches.

All applications for PhD Studentships at the Babraham Institute need to be made using the University of Cambridge Graduate Application Portal regardless of funding source: https://www.graduate.study.cam.ac.uk/

Please see the “Applying for a PhD” pages on our website for further details of the application process: https://www.babraham.ac.uk/vacancies-training/phd-programme/phd-applications

Short-listed applicants will be invited to attend our Institute Graduate Open Day on Wednesday 22nd January 2020 for a series of interviews. This will give applicants an opportunity to meet Group Leaders and their research groups, as well as receiving a tour of our research facilities. Reasonable travel expenses will be paid to those invited.

Students will not be able to take up an award unless they meet all University eligibility criteria and are successful in securing admission to the University. In addition, they will not be able to apply for a visa (if needed) until they hold an unconditional offer from the University.
 

Further Information

References
Microglia require CD4 T cells to complete the fetal to adult transition. Pasciuto, Burton, Rajan, Lagou, Theys, Roca, Prezzemolo, Brajic, Whyte, Callaerts-Vegh, Yshii, Mancuso, De Strooper, Dooley and Liston. Manuscript in preparation.

Pierson, Cauwe, Policheni, Schlenner, Franckaert, Berges, Humblet-Baron, Schonefedlt, Herold, Hildeman, Strasser, Bouillet, Lu, Matthys, Freitas, Luther, Weaver, Dooley, Gray and Liston. Nature Immunology 2013.

Contact Details

If you would like more information, or have any questions not answered on our website or the University of Cambridge Graduate Admission site, please contact us:
Graduate Studies Assistant, Babraham Institute, Babraham Research Campus, CB22 3AT or email to babraham.graduate@babraham.ac.uk