(MRC DTP) Delivering clinical proteomics to the clinic: high-throughput, targeted protein quantification.

There is a growing need for the discovery of novel biomarkers to provide detail on patient status, for rapid or early diagnosis of disease, and for stratification of cohorts for research or treatment. Proteins provide a valuable source for potential biomarkers. Most medicines target proteins, and of over 350 FDA-approved clinical tests, over half are for proteins. New advances in technology, primarily mass spectrometry (MS) for protein quantification enable the identification of potential disease biomarkers. However, there remains a ‘translation gap’ where methods used for this discovery, which focus on measuring many proteins in small numbers of samples, are generally unsuitable for rapid testing of a few target proteins in large sample numbers. As such, testing proteins in large clinical populations by MS remains difficult. Most clinical assays for protein levels therefore rely on antibodies, which can suffer issues of non-specificity, limited dynamic range, or interferences. The ability to use MS in this setting would be game-changing. However, protein quantification by MS in the clinical diagnostic laboratory is technically challenging.

This project aims to overcome some of these hurdles by using a combination of existing and novel methods to build a new type of protein quantitation workflow, which will allow high throughput analysis of protein biomarkers in plasma in an integrated platform which adheres to international guidelines for clinical assay development. Such technology will accelerate biomarker validation, and thus increase the opportunity for improved measurement of biomarkers or biomarker panels in the clinical laboratory.

As a paradigm for this project, the student will develop a novel assay for levels of Tau protein in patient plasma. Current assays for Tau are affected by its variable modification, and a lack of sensitivity in standard immunoassays (Henricksen et al, Alzheimer’s & Dementia 10 (2014) 115–131), although levels of circulating Tau have been proposed as being useful in the early detection of Alzheimer’s Disease, prediction of the degree of damage following stroke, or in cases of brain ischemia or traumatic brain injury. Tau levels will be assayed in plasma samples obtained from local collaborators in the areas of dementia and stroke, with the dual aims of showcasing this new technology for the reproducible and rapid measurement of proteins in plasma samples, and of investigating Tau as a biomarker in a range of neurological conditions.

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http://www.manchester.ac.uk/research/r.unwin/