Old age macrophages? Programming distinct immune behaviours across the lifecourse

Details

The white blood cells known as macrophages are a highly heterogeneous population of cells and this diversity is necessary for their plastic responses to a changing microenvironment and a wide-range of required functions in vivo. These cells are fundamental for development, homeostasis and defences against infections and altered self. Their dysfunction causes or exacerbates the majority of human disease conditions, especially those with an inflammatory component, including cancer, neurodegeneration, atherosclerosis and chronic inflammatory conditions such as COPD. Furthermore, as we age. our immune system declines in its efficiency, due to processes including inflammageing and immunosenescence. Therefore, interventions that enable manipulation of immune cells and their function will have wide-ranging therapeutic application across the lifecourse.

Given the complexity of the human innate immune system, and the difficulties of working in vivo and genetic redundancy in vertebrates, simpler model organisms provide an attractive platform to investigate control of heterogeneity and how it impacts normal immune function.

Drosophila melanogaster (fruit flies), has been widely used to study the innate immune system and contains a blood cell population dominated by macrophage-like cells. Recent scRNAsequencing work and our own reporter-based approaches (Coates et al., 2021) indicate that fly macrophages are highly heterogeneous, but we do not yet understand how these different subpopulations are specified or controlled.

In this project, you will build on our transcriptomic profiling of macrophage subpopulations and compare those results with vertebrate data (Baidžajevas et al., 2020). This work has already identified key transcription factors hypothesised to define these subpopulations - both in terms of their ontology and their altered function. You will identify additional candidates and interactors/downstream regulators via bioinformatic approaches. You will use the fly as a high-throughput screening platform to characterise immune phenotypes. Ultimately you will translate your findings into vertebrates using mammalian macrophage cell culture approaches in which the 2nd/3rd supervisors are expert.

This project will suit applicants from a diverse range of backgrounds in, including training in cell biology, developmental biology, genetics and immunology. The successful applicant will display a passion for live imaging/microscopy and an appreciation for the use of model organisms in biomedical research. Our labs are part of the Bateson Centre (https://www.sheffield.ac.uk/bateson) and School of Medicine and Population Health at the University of Sheffield. We form part of a critical mass of innate immunity researchers combining genetic and imaging-based approaches making use of superb facilities such as the Wolfson Light Microscopy Facility, and Sheffield Drosophila and Zebrafish Facilities. Sheffield is a fantastic place to live and study and we’d love you to consider joining our dynamic, fun and diverse team. Please do not hesitate to make informal enquiries via email (i.r.evans@sheffield.ac.uk).

Entry Requirements:

Candidates must have a first or upper second-class honours degree or significant research experience.

How to apply:

Please complete a University Postgraduate Research Application form available here: www.shef.ac.uk/postgraduate/research/apply

Please clearly state the prospective main supervisor in the respective box and select Infection, Immunity and Cardiovascular Disease as the department.