Background: Over the last 30 years technological advancements in the fabrication of micro electrodes have permitted in-depth probing of cellular chemistry. However, congruent evolution of imaging technology to probe the effects of biochemical environment on metabolism and thus cellular viability in in-vivo tissue have not kept pace. Imaging metabolic function/dysfunction in the body usually requires radioactive tracers. The engineering of less invasive chemical sensors for the in-vivo observation of real-time fundamental processes associated with metabolism is crucial in modern life sciences to understand both health and disease. Magnetic Resonance Imaging (MRI), although often mistakenly presumed to lack the necessary sensitivity to achieve the required spatial resolution to image cellular metabolism, can rise to meet this challenge.
Objectives: The project will test the hypothesise that MRI can be used to investigate i) elevated ionic sodium Na+ levels in diseased/healthy tissue and ii) the associated effects on metabolism; through application/utilisation of:
• 23Na (X-nuclei) MRI to monitor tissue changes in Na+ concentration pre & post application of compounds to block specific Na+ transporters and channels (e.g. VGSCs and NHE1).
• Novel Magnetic Resonance Targeting (MRT) to improve the efficacy of ionic channel blockers and further differentiate biochemical environments.
• York developed SABRE-RELAY hyperpolarised 13C-pyruvate to monitor associated cellular metabolism in healthy and diseased tissue (e.g. tumour xenografts).
Novelty: This multidisciplinary project will for the first time bring together three innovative MRI methods to deliver a pioneering minimally invasive toolbox which can help further our mechanistic understanding of the effect if biochemical environment of cell viability in whole organs in-vivo.
Experimental Approach: We will study the ionic microenvironment of different tissues (both healthy and diseased e.g. brain/tumour xenografts) in-vivo using preclinical high field MRI (specifically 1H and 23Na) in cell phantoms and rodent models. Tissue ionic microenvironment will be altered via application of compounds to block specific ionic transporters and channels (e.g. VGSCs and NHE1). MRT will be used to increase the efficacy of such an approach. Associated metabolic changes will be probed with novel hyperpolarised MRI techniques. Data will be used in mathematical models (one way and two-way exchange models) to extract kinetic parameters/rate constants.
Timeliness: All three of the proposed MRI methods are new/novel. 1) With advancements in imaging gradient switching times, and high field MRI systems helping reduce scan times, application of 23Na MRI has recently been rediscovered for whole body imaging. 2) It was recently shown that the imaging gradients inherent in all MRI scanners can be re-utilised to direct magnetised compounds to tissue sites for an ~800% increase in uptake. It is hypothesised that following successful MRT Na+ tissue concentration would be further reduced and could be measured with 23Na MRI. 3) The MR detection of pyruvate to lactate conversion as a marker of associated metabolic dysfunction will be monitored over time using DNP or SABRE-RELAY hyperpolarised 13C NMR; a new and recently formulated method developed at York University.
National Importance: The project aligns with the 2015 UK government Quantum technologies Strategic Advisory Board; the goal of which was to aid early adopters in medical diagnostics. The project fits to Healthcare Technologies priority areas accelerating translation of new/novel MR methods to healthcare applications. The project aims to use advances in physical/chemical sciences to understand the fundamental underpinnings of ionic microenvironments in health and disease and therefore aligns directly with the University of York Health and Wellbeing research theme. The application of hyperpolarisation in MR is a supported research theme within the department of Chemistry.
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You should expect hold or expect to achieve the equivalent of at least a UK upper second class degree in Chemistry or a related subject. Please check the entry requirements for your country: https://www.york.ac.uk/study/international/your-country/
This project is available to students from any country who can fund their own studies. The Department of Chemistry at the University of York is pleased to offer Wild Fund Scholarships. Applications are welcomed from those who meet the PhD entry criteria from any country outside the UK. Scholarships will be awarded on supervisor support, academic merit, country of origin, expressed financial need and departmental strategy. For further details and deadlines, please see our website: View Website