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Are metabolites generated by the microbiota key to a young immune system?


Project Description

By 2050, the world’s population aged >60 years is expected to be 2 billion, up from 900 million in 2015, a major concern for the individual and for society.One of the contributing factors is ageing of the immune system. Aged individuals are less efficient at fighting infections and malignancies, have reduced capacity to respond to vaccinations. The mission of our ageing research is not to improve life span but health span, ie to reduce the burden of age-related diseases. Evidence is emerging that just a handful of cellular processes malfunctioning with age underlie these diseases. One of these processes is autophagy, the main mechanism by which cells remove cellular waste. Over the years, we have demonstrated a role for autophagy in different types of immune cells.We found that autophagy declines with age in immune cells. Cells start to accumulate material that cannot be digested, which stops them from executing their function and they produce inflammatory cytokines in excess. When we re-introduced autophagy with the polyamine spermidine, immune cells were rejuvenated, in particular memory CD8+ T cells3. Subsequently we uncovered a novel molecular pathway that controls autophagy downstream of the polyamines (Zhang et al, 2018 biorXiv).

A major source of polyamines is the gut microbiota. It is known that the gut microbiota is able to modulate host metabolism and immunity through the release of metabolites.In humans, the core microbiome is significantly different between old and young but the key metabolites maintaining a healthy lifespan have not been identified. In this DPhil project, we will address if autophagy and thereby immune responses are maintained by the metabolites produced by gut bacteria. We will test if our novel rejuvenating pathway can be recovered with microbiotic bacteria genetically engineered with state-of–the-art techniques to produce in excess polyamines or other identified metabolites. There is an increasing interest in using microorganisms as probiotics, either in fermented dairy products or formulated as tablets. However, convincing scientific data supporting their health claims are scarce. This study will help to understand at the metabolite level how the microbiome contributes to ageing.

ENVIRONMENT

The Kennedy Institute is a world-renowned research centre, housed in a brand new, state-of-the-art facility at the University of Oxford.The Simon lab consists currently of 4 postdocs, 2 DPhil students (both in their second year) and 2 graduate students and is well funded by the Wellcome Trust. It is a small, friendly and very international lab. While lab members are ambitious, team spirit is being encouraged. Every DPhil student (8 so far) has had the opportunity to write a review, and has published a first author primary paper. We collaborate locally, nationally and internationally. The presentation of data at conferences is encouraged. We regularly welcome MSc students and other short-term students in the lab, so there will be opportunities to train your supervision skills

TRAINING

Training will be provided in techniques including genetically engineering of gut microbiota, defining the metabolome, transcriptome and translatome (and related bioinformatics), and immunological techniques such as multi parameter flow cytometry, histochemistry, confocal microscopy.You will attend regular seminars within the department and in the wider University. You will be expected to present data regularly in lab meetings and in departmental progress report seminars. You will have the opportunity to work closely with collaborating groups interested in the microbiome (Fiona Powrie, KIR and Justin and Erica Sonnenburg, Stanford). A core curriculum of lectures is offered in the first term to provide a solid foundation in a broad range of subjects including musculoskeletal biology, inflammation, epigenetics, translational immunology, data analysis, statistics and the microbiome.

Funding Notes

Interested applicants should have or expect to obtain a first or upper second class BSc degree or equivalent, and will also need to provide evidence of English language competence. The University requires candidates to formally apply online and for their referees to submit online references via the online application system. The application guide and form is found online and the DPhil or MSc by research will commence in October 2019.

References

Riffelmacher, T.et al.Autophagy-Dependent Generation of Free Fatty Acids Is Critical for Normal Neutrophil Differentiation. Immunity47, 466-480, doi:10.1016/j.immuni.2017.08.005 (2017).

Clarke, A. J., Riffelmacher, T., Braas, D., Cornall, R. J. & Simon, A. K. B1a B cells require autophagy for metabolic homeostasis and self-renewal. J Exp Med215, 399-413, doi:10.1084/jem.20170771 (2018).

Puleston, D. J.et al.Autophagy is a critical regulator of memory CD8(+) T cell formation. Elife3, doi:10.7554/eLife.03706 (2014).

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