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Type 1 diabetes; novel insights from molecular analysis of single B cells.

  • Full or part time
  • Application Deadline
    Monday, November 25, 2019
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

About This PhD Project

Project Description

Overview:
The University of Bristol is offering a 3.5 year full time PhD to start in 2019. 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 (£15,009 p.a. for 2019/20, updated each year). Additional research training and support funding of up to £5,000 per annum is also available.

Additional research and training funding is available over the course of the programme. This will cover costs such as research consumables, courses, conferences and travel. Additional competitive funds are available for high-cost training/research. The studentship is based at the Bristol Medical School http://www.bristol.ac.uk/medical-school/

This is a project at the cutting edge of molecular immunology. You will be supervised by Prof Kathleen Gillespie (Diabetes and Metabolism, Univ Bristol); Prof Sarah Richardson (Islet Biology Exeter, College of Medicine and Health, Univ Exeter) and Dr Danijela Tatovic, Prof Colin Dayan and Prof Susan Wong (Infection and Immunity, School of Medicine, Cardiff Univ).

Background

Recent studies have demonstrated that B lymphocytes play a key role in type 1 diabetes (T1D – previously known as juvenile onset of insulin-dependent diabetes). Studies from our group have shown that islet autoantibodies, derived from B cells, can be used to predict over 90% of the children who will go on to develop T1D. Recently we have shown that the presence of certain B cell subsets in the pancreatic islets is associated with disease onset earlier in childhood. A critical gap in our knowledge however is that we cannot predict when a child with autoantibodies will develop diabetes. Until now, it was only possible to study autoantibodies in serum without being able to separate individual immunoglobulin molecules and only a limited number of characteristics of individual B cells could be studied. Recent developments of single cell “bar coding” and analysis (using Nanostring and 10x technology) allows the location on human type 1 pancreatic tissue and whole transcriptome data from a single cell to be determined. Assay platforms have become available to sequence both the heavy and light chains of individual B cells. Our group has developed techniques to isolate antigen specific B cells and we also have access to precious material from human pancreases and lymph nodes from subjects with T1D as well as skin from sites of islet specific antigen immunisation.

Aim and approach:
In this project, B cells from these sites will be isolated by laser-capture microscopy and bar coded for single cell transcriptomic analysis and B cell receptor (immunoglobulin) sequencing. The heavy and light chains will then be co-expressed to generate secreted monoclonal antibodies whose specificity can be determined in established in-house assays. In this way, the project will not only generate some of the first human monoclonal antibodies to islet-antigens for detailed analysis, but also provide a whole transcriptomic profile of confirmed antigen-specific B cells. Developing this technology will provide key information on the role of B cells in T1D pathogenesis but also identify B cell subsets that can be targeted for immunotherapy.

This is a highly original project that will provide training in novel technologies including single cell transcriptomics and advanced flow cytometry for antigen specific B cell isolation. In addition to exposure to bioinformatics and sequencing technology, the student will learn molecular biology expression techniques and the characterisation of monoclonal antibodies. Several of the techniques involved are challenging, but a range of contingency options will be available.
Environment
The successful candidate will have access to three of the leading laboratories in T1D research in the UK and internationally, with support from more than 15 post-docs and leading scientists. Access to the human material is well established in these laboratories including a unique world-wide collection of pancreatic material from recently-diagnosed T1D in adults and children (Exeter) and collaboration with the network for Pancreas Organ Donors (nPOD) in the USA and the recently MRC funded UK QUOD network (Cardiff/Bristol). The supervisory network leads the UK T1D Immunotherapy Consortium (Cardiff) and its B cell mechanistic core laboratory (Cardiff), UK Diabetes TrialNet (Bristol), as well as hosting the internationally recognised UK islet cell antibody testing laboratory (Bristol) and has been collaborating on projects for over 10 years. The majority of the time will be based in state-of-the-art University of Bristol laboratories in Learning and Research, based at North Bristol Trust. Specialist experimental protocols will be carried out in the laboratories of co-supervisors in Exeter and Cardiff and monthly meetings with all supervisors will be held by videoconference as well as regular face to face meetings. Bristol Medical School is a highly collaborative and supportive research environment where the PhD student will be part of the cross-disciplinary cohort of PhD students and will be able to take advantage of the training opportunities including journal clubs, reading groups, researcher meetings. The student will also have access to an internationally recognised programme of short courses throughout each year of the PhD.

Candidate requirements

Applications are welcome from high performing individuals across a wide range of disciplines closely related to natural sciences, biostatistics, genetics, biochemistry, mathematics and computer science who have, or are expected to obtain, a 2.1 or higher degree. Applications are particularly welcome from individuals with a relevant research Masters degree.

How to apply

Please make an online application for this project https://www.gw4biomed.ac.uk/doctoral-students/)

Contact: Kathleen Gillespie;

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