Tackling ageing in the gut: investigating the contribution of macrophages in the intestinal stem cell niche to gut maintenance and repair

Details

Ageing of the gut is an important contributor to multimorbidities of the elderly, including frailty, and mental decline. However, the specific cellular and molecular mechanisms driving gut degeneration with ageing and how these lead to specific clinical outcomes are still unclear. Nevertheless, evidence suggest that age-related changes in the gut, such as inflammation and microbiome, have the potential to drive ageing in other tissues, including degenerative diseases in the brain, namely Alzheimer’s.

Accordingly, increased gut permeability with ageing is a predictive biomarker for frailty and death. Therefore, understanding the mechanisms driving intestinal degeneration with ageing could identify therapeutic targets to prevent dysfunction in multiple tissues. This PhD proposal aims to characterise how the macrophage immune component of the intestinal stem niche changes with ageing and in the absence of telomerase, and how these correlate with gut repair capacity, using zebrafish and human samples. This is a multidisciplinary project, with state-of-the-art methodology, from advanced microscopy, immunofluorescence, bioinformatics and in vitro work with the possibility of a placement in Oxford.

The student will:

1) participate in a multidisciplinary environment, bridging the Bateson Centre and Healthy Lifespan Institute, benefitting from excellent seminar series and PhD-cohort support. The student will also spend time in the 3rd supervisor’s lab (Bristol) and with our industry collaborator (Oxford), where they will broaden their professional network and interdisciplinary research skills.

2) Benefit from mentoring and supervision by a world-leader in human organoid systems for clinical translation, Dr. Boccelatto, based at the Ludwig Institute in Oxford, a private Industry in Cancer Science AND Professor Fiona Ducotterd, head of drug discovery team at the Charity Alzheimer’s Research UK Drug Discovery Institute at University College London.

3) Learn a diversity of state-of-the-art lab skills and technology relevant for ageing research: advanced microscopy and LCM, Omics and bioinformatics, in vivo work using zebrafish (Home Office PIL course), histopathology, quantitative analysis and in vitro work with human-derived tissue.

Entry Requirements:

Candidates must have a first or upper second class honours degree or significant research experience. Candidates must be prepared to be trained in and use zebrafish as an animal model, according to Home Office regulations.

How to apply:

Please complete a University Postgraduate Research Application form available here: https://www.sheffield.ac.uk/postgraduate/phd/apply/applying

Please clearly state the prospective main supervisor in the respective box and select ‘Oncology & Metabolism’ as the department.

Enquiries:

Interested candidates should in the first instance contact Dr Catarina Henriques, [email protected]. Proposed start date - October 2024