During development, groups of cells communicate with each other using protein messengers that are secreted from one cell and bind to receptors on neighbouring cells. One important family of protein messengers are called Wnts (pronounced wints). When the message is received, the responding cell switches on a number of genes in its nucleus that in turn bring about changes to processes such as growth and cell type. The connections inside the cell that transmit the Wnt signal from the cell surface to the nucleus are very important since they control how the signal is amplified and aimed at the right genes. The proposed research will use a method to the order in which connecting Wnt signalling components function inside the cell. The basic idea is to use a very sensitive cells that have been engineered to send out a burst of light when the Wnt signal is active in the nucleus. We then use a new method called RNAi to remove proteins that might be Wnt connecting components. If the protein IS required, the burst of light will be lost. This question is asked again and again for many genes using robots to speed up the process. We can ask whether and how many genes are required for Wnt signalling Once we know which proteins are involved in the Wnt pathway, we can study how they work and how they control animal development.

The use of metal complexes in molecular imaging is well established. The availability of technetium-99m from a commercial generator coupled with the properties of this radioisotope (technetium-99m emits 140 keV gamma-ray with 89% abundance) has meant that technetium-99m has become the preferred radioisotope for SPECT imaging. The 6 hour half life is attractive since it allows sufficient time for radiosynthesis and distribution of labelled compounds to imaging centres. The design of chelates and the corresponding metal-complexes plays a significant role in the development of new tracers. The properties of the metal-chelate moiety (e.g. lipophilicity, charge, size) can greatly influence the in vivo characteristics of the final labelled candidate. Another key factor of the design of chelates relates to the radiolabelling conditions utilized - for example, the physiochemical properties of the macromolecule will influence the choice of conditions. For example the pH and temperature can impact on the nature of the macromolecule (aggregation and stability). The labelling conditions (and consequently the design and modification of the chelate) need to be 'tuned' to the properties of the macromolecule. One of the critical properties of the resultant metal-chelate complex is that it is highly stable in vivo. Although, there have been significant developments in the use of chelates in technetium chemistry, recently the requirement to label more complex and larger macromolecules (> 10 kDa) has demonstrated the need to develop alternative chelates. Proposed Programme: (i) Novel chelate synthesis - the IC Chemistry Department and GEHC have considerable experience in this area. The plan is to design chelates which are suited to a broader range of labelling conditions e.g. pH, temperature. Tailored, multifunctional ligands can allow the modification of reactivity and lipophilicity, stablisation of specific oxidation states and investigation of substitution inertness. They can also play an integral role in muting the potential toxicity of a metallodrug to have a positive impact in areas of diagnosis and therapy. To date, ligand coordination to 99mTc has generally utilized N2S2 or N4-donating atoms but within this project, wider and unexplored aspects of Tc coordination chemistry will be investigated in the search for compounds with increased specificity. Chelate motifs to be studied will include P2N2, P4N2, P(=O)2N2, P(=O)4N2, P(=S)2N2 or P(=S)4N2 donor sets, either within a macrocyclic structure or within an open-chained multidentate ligand, such as a functionalised tris(pyrazolyl)borate or similar tripodal species. Another novel facet will involve the incorporation of redox-active groups within the chelate framework i.e. ferrocene, quinolines, dithiolenes, in order to harness and exploit the rich oxidation state chemistry of technetium, focusing on biological and biomedical applications. (ii) Labelling conditions will be developed using Tc-99m. Parameters including reducing agents, pH, temperature, reaction time will be investigated. (iii) Metal-complex stability will be assessed using standard methodology (in vitro & in vivo) and will be compared against existing chelate including bis(amine-oxime), bis-amine-dithiol, tetra-amine and polypyridyl. (iv) Successful chelates will be conjugated onto biomolecules e.g alpha-v-beta-3 inegrin peptide (RGD), Octreotide the somatostatin receptor ligand and other novel macromoles from the GEHC library. Key disease areas for application of these probes will be in oncology, neurology and metabolic disorders. (v) Biological evaluation of the above labelled candidates will be carried out in collaboration with the biology groups. The biological studies will include biodistribution, metabolism and imaging of probe in a suitable animal model. These studies will be carried out at GEHC laboratories.

The global electricity network has recently been experiencing a large scale integration of renewable energy sources, mainly photovoltaic and wind. This transformation is driven by the need for a reduction of carbon dioxide emissions, to limit greenhouse effect and mitigate global warming at the same time improving security of the supply. Large coal power plants are the main contributors of CO2 emissions, and electricity demand is constantly growing, especially in large urban/industrial areas. In this scenario, renewable energies are the only viable alternative to reduced environmental impact and carbon footprint of the electrical system. The main drawback of renewable energies is that they are usually generated far from where the energy is consumed. Typical examples in the UK are offshore wind farms, harvesting energy in the North Sea and delivering it to the mainland. Installing wind farms offshore gives higher wind speed and minimises the environmental impact, but might result in hundreds of kilometres separating the generator and the users. When distance increases, traditional and well-established AC transmission technology becomes unsustainable for its high energy loss. High Voltage DC (HVDC) is the technology enabling bulk power transmission over long distances (>600km for overhead cables, >40km for submarine cables), thanks to its higher efficiency and lower cost. Compared to AC power transmission, DC transmission is more complex, relying on Power Converter stations to transform from AC to DC at the wind farm side and back to AC when power is delivered to the mainland. Major issues in the design of converter stations for HVDC are size, weight, cost, efficiency, and manufacturing/maintenance. The basic problem is that these converters, when based on conventional technology, can be as large as a medium-sized industrial building and as heavy as 10000 tons for a typical 1GW installation. This poses two main challenges, at both ends of the HVDC link: 1.Offshore challenge: installing large and bulk converters offshore increases the cost of the platform, and reduces competitiveness of offshore wind. In addition, construction, commissioning and maintenance of the converter are both complex and expensive. 2.Onshore challenge: the converter onshore is often located in densely populated areas where energy is needed but land is expensive and limited. Also, environmental and visual landscape impact are a concern. This project will propose compact power conversion topologies for offshore and urban stations that have reduced size, weight, cost and environmental impact while maintaining adequate performances. In addition, the commissioning phase will be taken into account in the explored topologies, in order to increase modularity at system level and reduce construction efforts. The topologies will be discussed with key industry stakeholders and compared to standard state of art solutions, to identify the most attractive option, and the result of this trade off will feed into three work packages: design of the proposed converter, computer simulation and construction of a laboratory demonstrator to prove the feasibility and functionality of the proposed technology.

Lung disease is the 4th largest cause of death worldwide and also creates a massive burden of ill health. Current methods for monitoring the extent and progression of lung disease such as chronic obstructive pulmonary disease (COPD) ans interstitial lung disease (ILD) are limited to anatomical information derived from high resolution CT scanning or functional information from pulmonary function testing. There is a major need for a method to noninvasively monitor regional variations in ventilation and gas transfer using nonradioactive techniques in order to provide a sensitive way to aid diagnosis and monitor therapy. The aim of this proposal is to utilize advances made at the University of Nottingham in the field of hyperpolarized gas technology, coupled with state of the art magnetic resonance (MR) imaging, to develop new, clinically valuable methods to monitor the extent and progress of lung disease in patients.This proposal will achieve this aim through a new collaboration between internationally recognized researchers in the Sir Peter Mansfield MR centre (Prof P Morris, Dr M Barlow and colleagues) and a clinical academic with specific expertise in lung disease (Prof IP Hall), both in the University of Nottingham, and collaborators at GE Healthcare, a major international manufacturer of clinical imaging equipment. Specifically, during this programme of research we will (i) optimize methods for the standardized production of hyperpolarized Xenon to underpin these novel imaging techniques, (ii) develop equipment, software and MR techniques to achieve high resolution functional images of ventilation and gas transfer in normal subjects, and (iii) establish an academic imaging facility embedded in the Medical School to facilitate initial physiological imaging of both in and out patients with specific lung diseases in an appropriate clinical environment using optimized MR methodology. This project therefore offers the possibility of providing novel clinical tools for the diagnosis and monitoring of pulmonary diseases.

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.