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(MRC DTP) Characterisation of longitudinal peripheral immune cellular changes in vascular dementia


   Faculty of Biology, Medicine and Health

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  Prof Craig Smith, Dr J Grainger, Prof Stuart Allan  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

Stroke is a major cause of death and disability worldwide. In stroke survivors one of the most distressing complications is dementia, which occurs in up to a third of individuals within five years and impacts significantly on quality of life.

Dysregulated inflammatory and immune pathways are strongly implicated in the pathophysiology of cerebrovascular disease and have also been linked to dementia and cognitive impairment. Innate immune cells, such as microglia and monocytes, play a key role in the response to brain injury and are thought to modulate subsequent pathways involved in recovery and repair. We have recently undertaken detailed immunophenotyping of the peripheral blood myeloid compartment in acute stroke patients, and identified specific changes in dendritic cell and monocyte subsets. In preliminary studies, our collaborators have demonstrated that specific changes in peripheral innate cells in the acute phase of stroke correlate with subsequent cognitive impairment. Our overarching hypothesis is that innate immune alterations in the acute phase after stroke shape chronic maladaptive neuroimmune responses that compromise long-term structural and functional brain integrity, and contribute to the development of vascular dementia.

The main aim of this project is to Investigate the association between peripheral blood immune status after stroke, with a focus on myeloid sub-sets, and development of vascular dementia in patients. The project will align with an ongoing prospective cohort study of patients with acute ischemic stroke (Stroke-IMPaCT; https://stroke-impact.org/), with longitudinal follow-up, serial blood sampling, blood bio-banking, and clinical assessments, funded by a prestigious Leducq Foundation Transatlantic Network of Excellence Award (https://www.fondationleducq.org/). Serial blood samples will be drawn for evaluation of immunophenotype and function of myeloid subsets using state of the art multicolour flow cytometry, RNA sequencing and immunoassay of related plasma inflammatory markers. Computational immunology algorithms will be applied to the flow cytometric analyses and single-cell RNA sequencing. Relationships with baseline clinical factors and both cognitive and functional outcomes will be explored.

Comprehensive training will be provided in translational neuroscience, immunology and bioinformatics. The work will parallel pre-clinical studies within the Stroke IMPaCT network and benefit from interactions with leading stroke research laboratories. There will be opportunities to visit our collaborating groups to present data and learn emerging technologies and techniques. This project will provide novel insights into how the immune system is altered over time after stroke and how this relates to cognitive trajectory and possible therapeutic or preventative targets.

https://www.research.manchester.ac.uk/portal/craig.smith-2.html

https://www.research.manchester.ac.uk/portal/stuart.allan.html

https://www.research.manchester.ac.uk/portal/john.grainger-2.html

https://stroke-impact.org/

https://www.braininflamelab.org/

https://www.ncaresearch.org.uk/gjbrainresearch/

Entry Requirements

Applicants must have obtained or be about to obtain a First or Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in an appropriate area of science, engineering or technology.

How to Apply

To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the MRC Doctoral Training Partnership (DTP) website www.manchester.ac.uk/mrcdtpstudentships 

Applicants interested in this project should make direct contact with the Primary Supervisor to arrange to discuss the project further as soon as possible.

Equality, Diversity and Inclusion

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/


Funding Notes

Funding will cover UK tuition fee and stipend only. The University of Manchester aims to support the most outstanding applicants from outside the UK. We are able to offer a limited number of scholarships that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

References

1. Krishnan S, O'Boyle C, Smith C, Hulme S, Allan S, Grainger J, Lawrence CB (2021) A hyperacute immune map of ischaemic stroke patients reveals alterations to circulating innate and adaptive cells. Clinical & Experimental Immunology 203:458-471.
2. Hotter B, Hoffman S, Ulm L, Meisel C, Bustamante A, Montaner J, Katan M, Smith CJ, Meisel A (2021) External validation of five scores to predict stroke-associated pneumonia and the added value of blood-based biomarkers. Stroke 52:325-330.
3. Shuwa HA, Shaw TN, Knight SB, Wemyss K, McClure FA, Pearmain L, Prise I, Jagger C, Morgan DJ, Khan S, Brand O, Mann ER, Ustianowski A, Bakerly ND, Dark P, Brightling CE, Brij S, CIRCO, Felton T, Simpson A, Grainger JR, Hussell T, Konkel JE, Menon M (2021) Alterations in T and B cell function persist in convalescent COVID-19 patients. Med (N Y). 11;2(6):720-735.
4. Mann ER, Menon M, Knight SB, Konkel JE, Jagger C, Shaw TN, Krishnan S, Rattray M, Ustianowski A, Bakerly ND, Dark P, Lord G, Simpson A, Felton T, Ho LP, NIHR Respiratory TRC, Feldmann M, CIRCO, Grainger JR, Hussell T (2020) Longitudinal immune profiling reveals key myeloid signatures associated with COVID-19. Sci Immunol Sep 17;5(51):eabd6197. doi: 10.1126/sciimmunol.abd6197.
5. Wong R, Lénárt N, Hill L, Toms L, Martinecz B, Császár E, Nyiri G, Papaemmanouil A, Waisman A, Muller W, Schwaninger M, Rothwell N, Francis S, Pinteaux E, Denes A, Allan SM (2019) Interleukin-1 mediates ischaemic brain injury via distinct actions on endothelial cells and cholinergic neurons. Brain, Behavior, and Immunity 76:126-138.
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