The Bloomsbury Colleges | PhD Studentships | Studentships 2014 | The Evolution Of Immune Regulation: Comparative Phylogenetic And Protein Modelling Studies Of Regulatory Molecules Within The Animalia Kingdom
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The Evolution Of Immune Regulation: Comparative Phylogenetic And Protein Modelling Studies Of Regulatory Molecules Within The Animalia Kingdom

Principal Supervisor: Professor Oliver Garden, Royal Veterinary College

Co- Supervisors:

(1) Dr Adrian Shepherd, Birkbeck

(2) Dr Bradley Cobb, Royal Veterinary College

One of the hallmarks of the adaptive immune system in vertebrates is the ability to neutralise pathogens without causing autoimmune tissue damage. Peripheral mechanisms that involve the deletion or functional neutralisation of autoreactive T and B cells are key to this function of immune tolerance. Regulatory T cells (Tregs) are a major component of peripheral tolerance in multiple species and serve as a useful point of focus for the evolutionary interrogation of regulatory mechanisms. Foxp3, one of four members of the Foxp subfamily of Forkhead transcription factors, controls the differentiation and function of Tregs, operating within an ‘interactome’ of numerous transcription factors and chromatin regulators. While some of the binding partners of Foxp3 are known (e.g. c-Rel, Tip60/HDAC7, Eos), its structural characteristics and the contribution of its various domains to regulatory function are incompletely understood. Furthermore, a number of other molecules play an important role in immune tolerance, yet their evolutionary relationships have not yet been explored.

We hypothesise:

  1. That there is an evolutionary hierarchy of molecules associated with peripheral tolerance, with functional redundancy of Treg-associated molecules across different phyla.
  2. That the structure of Foxp3 and other molecules associated with peripheral tolerance comprises: (i) regions subject to purifying selection, representing parts of the molecule involved in evolutionarily ancient protein:protein or protein:DNA interactions crucial to core function, and (ii) regions subject to diversifying selection, representing parts of the molecule that have evolved to assume divergent functions within different phyla.

We will model the structural consequences of selection within these molecules and re-create in silico the respective ancestral sequences of proteins showing diversifying selection. Focusing on Foxp3, we will assemble the gene encoding the ancestral protein and test its functional activity in vitro by transducing CD4+ T cells with an appropriate construct, assessing regulatory function in standard suppression assays.

Candidate Requirements

This exciting project triangulates the disciplines of bioinformatics, evolutionary biology and immunology. The successful candidate will receive a thorough grounding in phylogenetics and protein modelling, while gaining knowledge of a translationally relevant branch of immunology that has ramifications for autoimmune, allergic and infectious disease, as well as to cancer and transplantation medicine. The candidate will also be trained in molecular biological and cellular immunological techniques, and receive an outstanding training in transferable skills through the RVC Graduate School and Birkbeck.

Applicants will have a working knowledge of a variety of bioinformatics tools and have a passion for applying these to biological questions of translational relevance. Demonstrated interest in evolutionary biology and/or immunology is desirable.

Applicants should have a First or Upper Second Class BSc degree in a discipline relevant to the course of study. Postgraduate training in bioinformatics or evolutionary biology with a working knowledge of phylogenetics (e.g. a relevant MSc) is essential if the applicant's first degree was in a biological, biomedical or other scientific discipline without a substantive bioinformatics component.

The successful candidate will be an excellent communicator, pro-active and able to take the initiative in advancing this area. He or she will have a passion for presenting and publishing his or her work, and will be an effective and collegial team player.

Key references

  1. Andersen, KG, Nissen, JK and Betz, AG (2012) Comparative genomics reveals key gain-of-function events in Foxp3 during regulatory T cell evolution. Frontiers in Immunology 3: 113
  2. Garden, OA, Pinheiro, D and Cunningham, F (2011) All creatures great and small: regulatory T cells in mice, humans, dogs and other domestic animal species. International Immunopharmacology 11: 576-588
  3. Thornton, JW (2004) Resurrecting ancient genes: experimental analysis of extinct molecules. Nature Reviews Genetics 5: 366-375
  4. Vent-Schmidt, J, Han, JM, MacDonald, KG and Levings, MK (2013) The role of FOXP3 in regulating immune responses. International Reviews of Immunology doi: 10.3109/08830185.2013.811657

Further details about the project may be obtained from:

Principal Supervisor: Professor Oliver Garden, ogarden@rvc.ac.uk; http://www.rvc.ac.uk/staff/ogarden.cfm

Co- Supervisors:

(1) Dr Adrian Shepherd, a.shepherd@mail.cryst.bbk.ac.uk, http://people.cryst.bbk.ac.uk/~ubcg60a/

(2) Dr Bradley Cobb, bcobb@rvc.ac.uk, http://www.rvc.ac.uk/Staff/bcobb.cfm

Further information about PhDs at the Royal Veterinary College is available from:

http://www.rvc.ac.uk/Postgraduate/Research/PhD/Index.cfm

Application forms and details about how to apply are available from:

http://www.rvc.ac.uk/Postgraduate/Info/HowToApply.cfm#research

Postgraduate Admissions Officer (Research Degrees)

RVC Graduate School

researchdegrees@rvc.ac.uk

0207 468 5134

Applicants must apply on UKPass and will also need to upload:

  1. a Curriculum Vitae;
  2. a personal statement explaining why they would like to undertake this particular project;
  3. a copy of their degree certificate(s);
  4. a transcript of their degree(s): this must be a certified translation if the original was not issued in English;
  5. two confidential references: these can also be submitted separately to the email address above.

Closing date for applications is 21st February 2014