To fully understand how nutrients in our diet are metabolised and promote health or risk of disease, we need to trace molecules such as sugars and fats around the body. The gold-standard method for this is by using stable isotope tracers. These are molecules that have been modified so that one or more of their atoms is replaced with a less common form of the atom (a stable isotope). These tracers are not radioactive; they are safe to give to humans, including children and pregnant women, and they have really shaped our understanding of nutrition and metabolism. For example, if a person ingests a meal containing a specific type of fat that has been labelled with a stable isotope tracer, we can follow the movement of this fat in and out of the blood over the course of time, and independently of other types of fat in the body. We do this by measuring the stable isotope tracer in a series of timed blood samples, using mass spectrometry. It is absolutely vital that we, and others, continue to use this technique to answer fundamental questions about how nutrition and physiology relate to human health, as outlined in the BBSRC's strategic plan. To this end, it is essential for us to update our old equipment (an isotope ratio mass-spectrometer, IRMS) with more reliable, next generation equipment. This will allow us to expand our analytical capability in the use of stable isotope tracer methodology at Surrey, and Nationwide. The more efficient software and hardware will allow us to operate the equipment in such a way as to maximise its use. This will involve widening access to the methodology, by increasing the available time on the machine, and by 'demystifying' the use of the technology through training and promotion. Our aim is train the next generation of undergraduate and postgraduate students, and visiting Fellows, in the use of stable isotope tracers. To help facilitate this aim, we have an industrial sponsor, LGC (The Laboratory of the Government Chemist), who will provide training on quality control procedures, and provide assurance that our measurements are of the highest standard. A major biological challenge of modern life is to understand how the Western diet impacts on human health. We are currently applying stable isotope tracers to address this challenge in three multi-centred studies funded by the BBSRC, one MRC-funded project and two BBSRC doctoral training partnership PhD projects that relate to the UK eating patterns. The first BBSRC study has been designed to better understand why some people's blood cholesterol is very sensitive to changes in the intake of dietary saturated fat, while others people's blood cholesterol shows little or no effect. We will be giving stable isotope labelled saturated fat to 'cholesterol responders' and 'non-responders' to trace the differences in metabolic pathways that might explain this variation in cholesterol response to saturated fat. In another BBSRC DRINC funded project, we will use potatoes that have the starch pre-labelled with an isotope label. This will help us to understand how chilling and reheating a mashed potato meal improves the body's handling of a particular type of starch in the potato. In a third BBSRC study, we will provide new evidence for the health effects of 'inter-esterified' fats that are being introduced by the food industry as substitutes for unhealthy, hydrogenated trans fats. An MRC funded project will examine the impact of the balance of food eaten in the morning and evening on metabolic and behavioural regulation during weight loss. This study will help to understand how energy balance can be modulated by altering meal timing. Finally, our BBSRC DTP students are measuring the intestinal handling of fructose in vivo and in a cell model, and investigating the regulation of enzymes that mediate the conversion of alpha linolenic acid in cooking oils, into long chain polyunsaturated fatty acids. Both of these studies would employ the use of a new IRMS.

Next-generation sequencing (NGS) technologies, such as Illumina's Solexa and Roche's 454 GS-FLX, offer orders of magnitude increases in throughput and decreases in per-nucleotide costs. Up to now these technologies have mostly been applied to qualitative studies such as gene discovery, complete-genome sequencing and genome re-sequencing. Recently they have begun to be applied to quantitative transcript profiling. Given their digital nature and great dynamic range, potentially these technologies could be used for measurement of a wide range of biological, environmental, and toxicological phenomena. For example, the abundance of important microorganisms (pathogens, biocontrol agents, bio-remediation agents) will be correlated with abundance of diagnostic sequence tags. Similarly, environmental load of toxins and other bio-active substances are expected to be correlated with changes in gene expression, heralding new fields of quantitative meta-transcriptomics and environmental transcriptomics. However, before we can leverage the potential of NGS technologies for such novel quantitative applications, there is a pressing need for proper testing and validation of the methods. Among the important questions are: [1] How much consistency is there between alternative methods (e.g. Illumina, 454, Quantitative PCR) [2] What is the degree of accuracy? That is, what is the degree of correlation between actual quantity and measurement? [3] Over what dynamic range is optimal accuracy maintained? [4] How robust are the technologies to increasingly complex mixtures of test material? [5] How robust are measurements with respect to the variations in DNA library preparation protocols? [6] What are the inherent biases of each method with respect to DNA sequence composition? [7] How reproducible are measurements made with NGS technologies? Other challenges include optimising methods for converting raw sequence reads into census counts. The student will have access to standard reference biological materials (well-characterised mixtures of two or more bacterial strains, for example) as well as Illumina (via Exeter) and 454 (via LGC) NGS platforms. The student will also have access to more established analytical methods such as quantitative PCR. The first step will be to devise a series of metrics of reproducibility and bias. As well as classical statistical approaches such as linear regression, the student will also make use of bioinformatics approaches, developed in the Studholme group, for tasks such as quality-filtering, mapping reads against reference sequences.

The bespoke Multiscale Metrology Suite, will combine powerful leading-edge detectors for measuring nanomaterial properties and transform the measurement of health nanotechnologies. We will build a modular system combining the latest in flow field fractionation technologies with mass spectrometry, Raman and light scattering detectors for the physical and chemical measurement of nanomaterial properties. The requested equipment will enable world-leading researchers at the University of Strathclyde, other UK academic institutions, and industry to accelerate their research into new technologies for healthcare applications and remain competitive in the global race for delivering new innovations in health. Moreover, this equipment will generate new research avenues and partnership opportunities that will create a step-change in the physical and chemical analytical capability and infrastructure for UK health nanotechnology research. This leading-edge suite will ultimately reduce the time and costs associated with delivering new diagnostics and drug treatments, improving quality of life and delivering much needed lifesaving drugs to patients. Strong partnerships with industry partners and government facilities will ensure that this national facility will remain globally-competitive and deliver innovations.

Dementia is currently diagnosed largely based on cognitive decline, while pathology starts years before symptom onset. To make progress in the development of effective drugs for dementia, there is an urgent need for biomarkers to enable precision health: for early and specific diagnosis and objective monitoring of disease progression. With its multidisciplinary team of scientists from academia, industry, and patient organisations, MIRIADE aims to train a new generation of scientists able to optimise and accelerate development of novel biomarkers for dementia. MIRIADE will integrate biomarker discovery data from multiple platforms and develop a Dementia Disease Map to enhance biomarker identification (WP1). We will develop assays for prioritized biomarkers (WP2), and selected markers will be clinically validated (WP3). We will study pre-analytical stability and validate against regulatory requirements (WP4) and develop a roadmap for optimal biomarker development (WP5). MIRIADE will thus establish an innovative biomarker-focussed cross-sectoral research and training programme that will equip ESRs with a unique combination of skills in big data analysis, biomarker assay development, innovation management, and a thorough understanding of medical needs. This programme will provide a new task force of scientists that are optimally trained to the accelerate the biomarker development for dementias and able to progress effective biomarker tools to the clinic.