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PhD Studentship - Old Red Blood Cells and the Immune System: Phagocytosis, Membrane Stiffness and "Eat-me" Signals

University of Exeter - Department of Physics, College of Engineering, Mathematics and Physical Sciences

Qualification Type: PhD
Location: Exeter
Funding for: UK Students, EU Students
Funding amount: £14,777
Hours: Full Time
Placed On: 1st October 2018
Closes: 23rd November 2018
Reference: 3223
 

Lead Supervisor:
Dr David Richards, Physics, University of Exeter

Additional supervisors:
Dr Charlie Jeynes, Biosciences, University of Exeter
Professor Karen Edler, University of Bath
Dr Ashley Toye, University of Bristol

Project Details

Background: Clearance of old red blood cells (RBCs) is essential for correct physiological maintenance of the blood. However, detailed mechanisms of this process remain a mystery, and it is unclear how RBCs “know” how old they are, and how this affects phagocytosis. Understanding this process is critical as premature RBC ageing and abnormal clearance is relevant to a range of common medical conditions such as sickle-cell anaemia, hemoglobinopathies, Gaucher’s disease, chronic kidney disease, diabetes and parasite infections.

The approach: Often the quickest way to make progress with this type of problem is to intimately combine experiments and modelling. Here, this will involve imaging phagocytosis of RBCs in the lab (with time-lapse microscopy of both real and artificial RBCs) and designing mathematical models (based on the immune cell shape). This combination means that the experiments can directly inform the model and that the modelling can suggest novel experimental directions. This approach will allow you to learn a highly-desirable combination of modelling and experimental skills, leading to excellent future career prospects.

Project plan: This cross-disciplinary studentship will be based at Exeter but will also involve spending time at both Bristol and Bath. It will include:

  1. Phagocytic assays. The engulfment of plastic beads will be examined to determine the role of target stiffness and coating on the efficiency and rate of phagocytosis. This will involve a dual-micropipette system and an environment-controlled Leica microscope.
  2. Modelling. A mathematical/computational model that involves membrane shape, receptor dynamics and intracellular signalling will be designed. For the first time, this model will involve target stiffness, which is critical for understanding RBC clearance.
  3. Design and culture of RBCs. Erythrocyte lines that overexpress CD47 (a “don’t eat me” signal) will be developed in Dr Toye’s lab in Bristol, before moving on to isolate primary white cells and utilise macrophage and neutrophil culture models.
  4. Image analysis. Building on the group’s existing custom-built software, image analysis software will be developed that automatically interprets the time-lapse images of phagocytosis, focusing on the rate of engulfment and the phagocytic cup shape.
  5. Properties of RBCs. Cultured RBCs under or overexpressing CD47 will be characterised (e.g. for turgidity, stiffness and membrane tension) with a variety of biophysical measures in Prof Edler’s and Dr Toye’s labs (e.g. using an automated rheoscope).

Outreach and public involvement will also play an important part of this studentship. You will work directly with Dr Silvia Bortoli (the Communities Engagement Manager within the Centre for Biomedical Modelling and Analysis at Exeter University) and the MAGPIEs (a group of lay people involved in medical research) in order to disseminate results and guide research.

To apply for this project, please complete the application form at cardiff.onlinesurveys.ac.uk/gw4-biomed-mrc-dtp-student-2019 by 5pm Friday 23 November 2018.

Funding Details

Full UK/EU tuition fees, as well as a Doctoral Stipend matching UK Research Council National Minimum (£14,777 for 2018/19, updated each year) for 3.5 years.

This studentship is funded through GW4 BioMed MRC Doctoral Training Partnership. It consists of full UK/EU tuition fees, as well as a Doctoral Stipend matching UK Research Council National Minimum (£14,777 for 2018/19, updated each year) for 3.5 years.

   
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