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(MRC DTP) Investigating the gut-brain axis: immunological consequences of brain disease

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  • Full or part time
    Dr M Hepworth
    Dr C Lawrence
    Dr D Brough
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Diseases of the central nervous system (CNS), including acute events (e.g. stroke) and chronic neurodegenerative diseases (e.g. Alzheimer’s disease), represent a significant healthcare burden and leading cause of mortality worldwide. Many diseases of the CNS were historically considered distinct from those caused by infection or immune dysfunction. However, recent advances have highlighted a key role for inflammation in the pathology and progression of brain diseases. While local inflammation mediated by microglia and invading inflammatory immune cells are now appreciated to contribute to disease pathogenesis in the brain, an increasing body of evidence has begun to implicate signals from peripheral organs, in particular the intestine, as important determinants of brain disease severity.

The intestine has been termed “the second brain” due to the high density of nerves that line the gut. The intestine contains a plethora of immune cells and hosts trillions of commensal bacteria, which produce metabolites with the ability to modulate disease pathogenesis in a wide range of peripheral organs - including the brain. This has led to the proposal of a bidirectional “gut-brain” axis whereby signals from the intestine (e.g. from microbes and/or the immune system) can alter brain function and disease outcome. Conversely, nervous stimuli originating in the brain may modulate intestinal immune function through enteric nervous system feedback.

Interestingly recent evidence indicates that ischaemic stroke induces dramatic changes in intestinal barrier function, the intestinal immune system and the balance of bacterial species present in the intestine. These findings suggest a previously unappreciated link between the intestine and the brain in disease and suggest stroke may have long-term consequences beyond the CNS. This project will investigate the molecular and immunological mechanisms through which the “gut-brain axis” contributes to disease pathogenesis. An increased understanding of this previously unappreciated area of biology may result in identification of novel targets for the treatment of neurological diseases, such as stroke or Alzheimer’s disease.

The successful student will receive a unique multidisciplinary training in neuroscience, immunology and microbiology by combining the expertise of the Hepworth (intestinal inflammation and immunology), Lawrence (stroke, Alzheimer’s) and Brough labs (Alzheimer’s, neuroinflammation). This project will utilize animal models of disease, immunological techniques and imaging, with the potential to incorporate next generation sequencing technologies.

The student will be based within the world-class Faculty of Biology, Medicine and Health (FBMH), with access to a wide range of core facilities and expertise from the supervisory team and the wider faculty.

http://www.mig.manchester.ac.uk/people/matthewhepworth/
http://www.mig.manchester.ac.uk/people/davidbrough/
https://www.research.manchester.ac.uk/portal/catherine.lawrence.html

Funding Notes

This project is to be funded under the MRC Doctoral Training Partnership. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the MRC DTP website www.manchester.ac.uk/mrcdtpstudentships

Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

References

1. The Central Nervous System and the Gut Microbiome.
Sharon G, Sampson TR, Geschwind DH, Mazmanian SK.
Cell, 2016

2. Commensal microbiota affects ischemic stroke outcome by regulating intestinal  T cells.
Benakis C, Brea D, Caballero S, Faraco G, Moore J, Murphy M, Sita G, Racchumi G, Ling L, Pamer EG, Iadecola C, Anrather J.
Nature Medicine, 2016

3. The mucosal immune system: master regulator of bidirectional gut-brain communications
Powell N, Walker MM, Talley NJ
Nature Reviews Gastroenterology and hepatology, 2017

4. Signals from the gut microbiota to distant organs in physiology and disease.
Schroeder BO and Bäckhed F
Nature Medicine, 2016

5. Translocation and dissemination of commensal bacteria in post-stroke infection.
Stanley D, Mason LJ, Mackin KE, Srikhanta YN, Lyras D, Prakash MD, Nurgali K, Venegas A, Hill MD, Moore RJ, Wong CHY.
Nature Medicine, 2016




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