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PhD Studentship (4 years) - Elucidating the molecular targets of bacterial nano-syringes

School of Biosciences

Location:  Aston University Main Campus
Basis:  Full Time
Closing Date:  23.59 hours GMT on Sunday 10 January 2021
Reference:  R200316
Release Date:  Tuesday 10 November 2020

Supervisor: Dr Alice Rothnie

Associate Supervisors: Dr Nick Waterfield (Warwick), Dr Alan Goddard (Aston)

Project Reference: MIBTP_Rothnie_Nano Syringes

BBSRC Strategic Research Priority: Microbiology, Structural Biology

Applications are invited for four year Postgraduate studentships, supported by the Midlands Integrative Biosciences Training Partnership (MIBTP) and Biotechnology and Biological Sciences Research Council (BBSRC). Up to 6 studentships are available.

The studentships are available to start in October 2021. 

Financial Support

The studentships include a fee bursary to cover the Home fees rate, plus a tax free stipend of at least £15,285 p.a (to rise in line with UKRI recommendation).

Overseas Applicants

Overseas applicants may apply for this studentship, and the home fees rate will be covered. UKRI funding will not cover the difference between UK tuition fees and international tuition fees; international tuition fee payers will be required to fund the fee difference themselves. MIBTP encourages international students with existing sources of funding (e.g. fellowships) to apply. The difference between home and international fees is £13,443 in 2020/21. Please confirm in your application how you will fund the fee difference."

Background to the Studentship

All MIBTP scholars will join a programme of skills training in year 1. Applicants are required to select an area of study (Sustainable Agriculture and Food, Understanding the Rules of Life, Renewable Resources and Clean Growth or Integrated Understanding of Health) but may join the programme with or without selecting a preferred project. Part of the skills training programme includes short rotation projects and students are able to choose a PhD project once they have experienced these differing research environments.

Potential PhD projects are provided to give applicants an idea of the breadth of research within MIBTP and specific research topics at Aston University. You can browse the other projects available here. Additional projects will become available during Year 1 and students can work with potential supervisors during their first year to develop a particular project.

Project Outline

The evolutionary ‘arms race’ between bacteria and their hosts has led to a wide range of sophisticated strategies and mechanisms which enable manipulation of host cells, often resulting in lethality. In recent years, particularly since the “Resolution Revolution” in the field of (cryo) Electron Microscopy, it has become apparent that these mechanisms can be extremely elaborate in the form of large macromolecule complexes, as well as more ‘conventional’ exotoxins etc.
 

Among the most elegant and well known of these bacterially-derived macromolecular complexes are the various “Secretion Systems”, particularly the Type 3 and Type 6, which effectively function as ‘harpoons’ embedded in the cell wall of the bacterium, which mediate cell-to-cell transfer of biologic material. More recently, structures which function as nano-scale ‘torpedos’ or syringes have been discovered, which are released by the bacteria into the extracellular milieu and are capable of acting ‘at a distance’. First discovered in Serratia and Photorhabdus species of bacteria, these so-called “Virulence Cassettes” are short gene clusters of approximately 16 genes, which contain everything necessary to produce, spontaneously self-assemble, and load with (typically toxic) cargoes, these remarkable entities. These ‘nano-syringes’ are evolutionarily related to bacteriophages, and function in a very similar way: Once free in the extracellular environment, they will diffuse and ‘seek out’ a target cell. One of the genes within the cassette gives rise to a so-called ‘tail fibre’ protein which, similar to bacteriophage, is responsible for binding to the relevant cell surface marker/receptor. Once bound, the nanosyringe vehicle contracts and an inner sheath of protein is propelled out to puncture the cell barrier. With the cell barrier pierced, the payloads contained within the nanosyringe vehicle are released into the cell cytosol.

One of the key features remaining to be elucidated is how the ‘nano-syringes’ interact with the target cell – what in the target membrane do their tail fibres bind to precisely? Work to date suggests possible candidates include cell surface (glyco)proteins, specific glycolipid components, or potentially some combination of the two. This collaborative project will combine expertise from the University of Warwick in producing and assaying the ‘nano-syringe’ tail proteins, with membrane expertise at Aston University. In particular polymer lipid particle approaches such as SMALPs (styrene maleic acid lipid particles) will be utilised in order to identify membrane components that bind to the purified tail proteins. These lipid particles are important as they will present membrane proteins within a native lipid bilayer environment, representing all possible molecular targets of the nano-syringes. Components that bind to the tail proteins will then be identified and investigated in more detail to study the affinity and specificity of the interaction.

These PVCs are being exploited by the new spinout company Nanosyrinx as potential delivery vehicles for biotechnological and healthcare applications. Advances made in understanding the targeting, and capacity to engineer/retarget this system will have immediate translational impact.

References:

Vlisidou, Isabella, et al. "The Photorhabdus asymbiotica virulence cassettes deliver protein effectors directly into target eukaryotic cells." Elife 8 (2019): e46259.

Jiang, Feng, et al. "Cryo-EM structure and assembly of an extracellular contractile injection system." Cell 177.2 (2019): 370-383.

Kube, Sebastian, and Petra Wendler. "Structural comparison of contractile nanomachines." AIMS Biophysics 2.2 (2015): 88.

Yang, G., et al. "Photorhabdus virulence cassettes confer injectable insecticidal activity against the wax moth." Journal of bacteriology 188.6 (2006): 2254-2261.

Pollock NL, Lee SC, Patel JH, Gulamhussein AA, Rothnie AJ* (2018) “Structure and function of membrane proteins encapsulated in a polymer-bound lipid bilayer.” BBA Biomembranes 1860(4); 809-817.

Person Specification

The successful applicant should have been awarded, or expect to achieve, a Masters degree in a relevant subject with a 60% or higher weighted average, and/or a First or Upper Second Class Honours degree (or an equivalent qualification from an overseas institution) in a relevant subject. Full entry requirements for Aston University can be found on our website.

Evidence of quantitative training is required. For example, AS or A level Maths, IB Standard or Higher Maths, or university level maths/statistics course. Full entry requirements for MIBTP can be found on their website.

Contact information

For further information on the advertised project, please contact Dr Alice Rothnie at a.rothnie@aston.ac.uk

Submitting an application

In order to apply for the MIBTP PhD studentship you must:

  1. Check your eligibility. 
  2. Complete a PhD application form on the Aston University website. From the drop-down options select School of Life and Health Sciences; October; Full time; Postgraduate Research; “Research Biomedical Sciences October 2021 Entry (Full-time)”.
  3. Notify MIBTP of your application by completing the online notification form; ensuring that you upload a current CV to the form.
  4. Review the MIBTP Data Privacy Policy to understand how we process your personal data.

When completing the Aston University application form, you will need to ensure to include the following documents:

  • Copies of your academic qualifications for your Bachelor degree, and Masters degree (if studied); this should include both certificates and transcripts, and must be translated in to English.
  • A personal statement*
  • A copy of your current CV
  • Two academic references
  • Proof of your English Language proficiency for non-Native English speakers, further details can be found on our website

*Please note that a project proposal is not required, however your Personal Statement should address your ability & knowledge of the research area.  Where applying for a specific project, please include the supervisor name, project title and project reference in your Personal Statement. 

If you require further information about the application process please contact the Postgraduate Admissions team at pgr_admisssions@aston.ac.uk 

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Further particulars and application forms are available in alternative formats on request i.e. large print, Braille, tape or CD Rom.

If you have any questions, please do not hesitate to contact HR via recruitment@aston.ac.uk


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