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Improving the functional imaging capability of SABRE hyperpolarised agents.


Project Description

Background
Signal amplification by reversible exchange (SABRE) is an established route for the efficient hyperpolarisation and therefore improved signal visibility of compounds with NMR. Recent developments in the SABRE process have now extended the variety of applicable compounds and chemical motifs (including pyruvate, glucose and other important bio-molecules). In turn this has opened up exciting potential clinical applications in spectroscopic imaging of function metabolism in-vivo, the realisation of which requires immediate imaging technology development.

In general, for all imaging nuclei, current spectroscopic acquisition methods are often inadequate in several aspects. Conventional excitation and refocusing RF pulses for spatial localisation of specific compounds can suffer from chemical shift mis-registration and image artefacts result confounding the data. Furthermore, the fast nature of capturing the quickly decaying hyperpolarised signals pushes peak RF power requirements to levels exceeding hardware limits thus potentially damaging expensive equipment. The short T1 relaxation times of the hyperpolarised agents also limits detection (a few seconds) to fast analysis of kinetic flux rates. Longer term measurements through dual probe labelling with optical markers will improve method efficacy for in-vivo basic science. Specific to 1H based SABRE, imaging in-vivo also requires optimal endogenous spin (water/fat) suppression as to not mask the compounds of interest. Partial suppression of the water pool during SABRE experiments can also provide valuable phase/frequency reference points for data analysis and an assessment of experimental success in cases in which all SABRE resonances are normally undetectable.

Objectives
To improve the scope of SABRE based imaging this project will:
• Develop and implement independent flip angle controlled spectral-spatial RF pulses to negate chemical shift mis-registration errors and to provide dual-band excitation with partial excitation of the water resonance and full excitation of the metabolites of interest.
• Implement strategies to lower RF power usage by at least 30% – including exploration and optimisation of phase modulation.
• Synthesise dual labelled agents with long life optical markers to allow both short term kinetic flux measurements (SABRE) and long term compound tracking (optically). This will improve the efficacy of in-vivo measurements and open opportunities for wider in-vivo basic research applications.

Experimental Approach
The SABRE process for relevant synthesised compounds (e.g. pyruvate/glucose/nicotinamide) will be optimised for both 1H and 13C based MR spectroscopic imaging. The proposed acquisition developments will be tested through the study of short/long term functional metabolic processes in brain using innovative concurrent preclinical high field 7T MRI and 2D optical imaging spectroscopy techniques. MR spectroscopic imaging using multi-band RF pulses will be tested/compared to imaging with standard narrow band RF pulses. MR and optical data will be used in mathematical models (one way and two-way exchange models) to extract kinetic parameters/rate constants.
Novelty: This multidisciplinary project will for the first time bring together innovative SABRE hyperpolarised chemistry, photochemistry based spectroscopy with advanced physical engineering of RF to deliver a pioneering research tool which can help further our mechanistic understanding of the effect if biochemical environment in brain across health and disease.

Training
The student will initially be introduced to chemical synthesis, catalysis and hyperpolarisation of the agents for the SABRE process. They will learn about 1H and X-nuclei NMR detection of these agents before expanding detection into the imaging regime. Training for imaging on high field 7T/9.4T preclinical MRI system and visible-wavelength spectroscopic photochemistry techniques to investigate in-vivo biological metabolism will be given. Development of programming techniques in the MATLAB framework will be essential for subsequent signal processing of resulting multimodal spatial-spectra data. Formal UK Home Office training for all in-vivo work will be sought.

All Chemistry research students have access to our innovative Doctoral Training in Chemistry (iDTC): cohort-based training to support the development of scientific, transferable and employability skills: https://www.york.ac.uk/chemistry/postgraduate/idtc/

The Department of Chemistry holds an Athena SWAN Gold Award and is committed to supporting equality and diversity for all staff and students. The Department strives to provide a working environment which allows all staff and students to contribute fully, to flourish, and to excel: https://www.york.ac.uk/chemistry/ed/. This PhD project is available to study full-time or part-time (50%).

This PhD will formally start on 1 October 2020. Induction activities will start on 28 September.

Funding Notes

This studentship is fully funded for 3 years and covers: (i) a tax-free annual stipend at the standard Research Council rate (£15,009 estimated for 2020 entry), (ii) research costs, and (iii) tuition fees at the UK/EU rate. Teaching studentships are available to any student who is eligible to pay tuition fees at the home rate: View Website
Other funding is available to those who are eligible for research council studentships: View Website
Funding may be provided by a Chemistry Teaching Studentship for which you should submit a separate application: View Website

References

Candidate selection process:
• Applicants should submit a PhD application to the University of York by 8 January 2020
• Applicants should submit a Teaching Studentship Application by 8 January 2020: https://www.york.ac.uk/chemistry/postgraduate/research/teachingphd/
• Supervisors may contact candidates either by email, telephone, web-chat or in person
• Supervisors can nominate up to 2 candidates to be interviewed for the project
• The interview panel will shortlist candidates for interview from all those nominated
• Shortlisted candidates will be invited to a panel interview at the University of York in the week commencing 10 February 2020
• The awarding committee will award studentships following the panel interviews
• Candidates will be notified of the outcome of the panel’s decision by email

Related Subjects

How good is research at University of York in Chemistry?

FTE Category A staff submitted: 47.06

Research output data provided by the Research Excellence Framework (REF)

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