NIHRDataInsights/HRCSData huggingface dataset:
Title: Wellcome Trust Clinical PhD Programme at the University of Dundee: 'The translation of quantitative proteomics applied to human disease'.
Funder: Wellcome Trust

Abstract: Recent research at the University of Dundee has led to the development of new methods that use quantitative, mass spectrometry-based proteomics techniques to assay biological mechanisms at a system-wide level. These approaches have been used to screen for novel human proteins involved in regulating basic cellular mechanisms and to assay and annotate protein properties, including subcellular localization, interaction partners, turnover rates and post translational modifications. My research project aims to translate these new state of the art quantitative proteomics methods in a clinical context and to compare results obtained in model human cell systems in the laboratory with changes observed in patient biopsy samples. Using model human cell lines, in which the expression of known tumour suppressor proteins and/or oncogenes can be modulated using small molecule inducers, the Lamond laboratory has identified human proteins which were previously unknown to be associated with mechanisms relevant to cell transformation. This includes the protein products of the human Formin 2 (FMN2) and MRFAP1 genes. I will characterise the expression of both these proteins in human malignancies, assess their suitability as biomarkers and explore how new, advanced proteomics methods can be used to identify other proteins whose expression is altered in human cancer tissue.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Wellcome Trust Clinical PhD Programme in International Health at the LSHTM: 'Cost-effectiveness of financial and non-financial incentives for the retention of physicians in the Malawian public health sector'.
Funder: Wellcome Trust

Abstract: Many countries in sub-Saharan Africa have physician densities lower than 10 per 100,000 population. Reasons include migration to the private sector and other countries. Various incentives have been offered to improve retention, including financial (e.g. accommodation) and non-financial (e.g. postgraduate training). Malawi has a physician density of only 1.1 per 100,000. The Malawian government and the UK recently implemented an innovative incentive programme. However, there is little evidence that these incentives are cost-effective. Aims To evaluate the cost-effectiveness of a range of incentives. To provide evidence for regional incentive programmes. Population Malawian physicians and final year medical students Design Phase one i) Literature and policy review ii) Qualitative fieldwork on valued incentives and motivating factors to inform design of discrete choice experiments. Phase two Discrete choice experiments (DCEs) comparing job scenarios offering different incentives. DCEs are an economic technique used when actual choices between goods are not possible. Instead, subjects choose between various scenarios. The trade-off made between different incentives indicates their relative importance to the individual. Phase three Cost-effectiveness analysis of incentives using DCE results and local costings. Outcome measures 1) Utility values for various incentives Cost per year gained in public sector for each incentive.


Research activity codes: 8.2 HEALTH AND WELFARE ECONOMICS
Health categories: GENERIC HEALTH RELEVANCE
Title: State-of-the-art facilities for structural biology at the University of Dundee.
Funder: Wellcome Trust

Abstract: Chemical structure determines shape, how one molecule interacts with another, how reactions occur and how chemicals contribute to biological function. The most powerful technique to elucidate accurate 3D structures, a picture of where atoms are positioned with respect to each other, is single crystal X-ray diffraction. The combination of a 3D model with biochemical/biological data allows us to understand what molecules contribute to many different aspects of life. We seek funding to establish a facility with a new X-ray generator, a modern detector coupled with a robotic sample changer and multi-angle light scattering equipment. This would greatly increase our efficiency at preparing complex assemblies, testing crystals and determining structures that contribute to studies of how nucleic acids and proteins control key life processes, of how proteins function to transmit chemical signals in or between cells, to construct the fungal cell wall, and the architecture of machines that bacter ia use to secrete poisons that contribute to disease. We generate structures of newly synthesized chemicals interacting with proteins to understand how these compounds can stick to a target. These structures guide efforts to make compounds that bind more efficiently and with the chemical properties that underpin drug discovery.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: An Anaerobic Crystallisation Facility at the University of Leicester.
Funder: Wellcome Trust

Abstract: Protein X-ray crystallography, along with associated biophysical approaches, has contributed enormously to our understanding of biological mechanisms and disease processes through the determination of the three-dimensional structures of proteins and their complexes. Even when pure protein samples are available, a limiting factor in these studies is obtaining diffraction quality crystals. A major difficulty is that the normal protein environment inside the cell is essentially devoid of oxygen, wh ereas during crystallisation exposure to oxygen in the air is normally unavoidable. This often results in damage to proteins during crystallisation. We are proposing to establish a facility that will allow us grow crystals in an oxygen-free, anaerobic environment. We will use a single crystal micro-spectrophotometer to allow us to monitor the oxidation state of the crystals before and during X-ray data collection. This is important because it is necessary to understand the redox state of the p roteins under study. This facility will greatly enhance our ability to address both fundamental biological questions, including many with relevance to mechanisms disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Investigation of the role of Nrf2 in man
Funder: Wellcome Trust

Abstract: Humans have evolved the ability to tolerate exposure to foreign chemicals, including drugs, which are generally safe in the majority of the population. Some individuals, however, may respond to drug treatment adversely, resulting in severe or possibly fatal reactions. The mechanism responsible for this adverse response is unknown, but may reflect an inability to launch a defence response when exposed to drugs. In mice, the defence response is regulated by a small number of key proteins that dire ct cells to manufacture a battery of enzymes and detoxicant proteins, aimed at neutralizing the initial chemical insult. Pre-eminent amongst these is the protein Nrf2, which, if genetically removed from mice, predisposes them to severe chemical toxicities. Whilst it is known that humans possess Nrf2, its importance in protection against chemicals has not been fully assessed because we lack the analytical tools to monitor the basal level of Nrf2 or its activation following chemical exposure. Thi s project aims to develop new markers for Nrf2 in man and to test them in patients exposed to established inducers of Nrf2. The development of biomarkers for Nrf2 will allow us to investigate how individuals differ in their ability to defend themselves against toxic chemicals.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: A systems approach to chemotactic cell sorting during development.
Funder: Wellcome Trust

Abstract: Dictyostelium is a simple model for multicellular development because only two major cell types are formed. We will label these two cell types using different colours and study how they first form a salt and pepper mixture, and then sort out from each other to form a simple pattern of celltypes that later develop into the stalk and the spores of a fruiting body. We will genetically alter cell properties believed to play a role in differential cell motion. In so called synergy experiments where w e mix differently labelled mutant and wild-type cells we will investigate how different properties affect sorting. Differences in individual cell movements, cell shape changes and intracellular distributions of the underlying molecular components will be quantified using advanced image analysis software. To interpret the complex data and inform new experiments we will use existing and novel mathematical models and predictions based on computer simulations. Key goals are I) to answer whether sort ing can result from differences in cell contractility, which affects the efficiency of cell movement II) to find evidence for or against involvement of differential cell movements in early chick development, as an example for vertebrate development with possible relevance for ultimately understanding human development.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Control of translation elongation factor eEF1A isoform switching.
Funder: Wellcome Trust

Abstract: Protein synthesis is essential for cell survival and is considered to be a basic housekeeping function. This means that the molecules that the cell uses to achieve protein synthesis are usually found in all different tissues regardless of their origin. We are studying a pair of molecules that, although they have a key role in protein synthesis, are found in specific, non-overlapping, cell types. One of these molecules, called eEF1A2, is only found in nerve and muscle cells; a particular strain of mice that have a deficiency of eEF1A2 develop a form of motor neuron disease. On the other hand, if eEF1A2 is switched on in cell types that don t usually have it, like breast and ovary cells, this can result in cancer. It is therefore very important to understand what controls whether specific cells turn eEF1A2 on or off.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: A novel resource for vertebrate developmental biology: transgenic chick embryos expressing fluorescent reporter genes.
Funder: Wellcome Trust

Abstract: The chick embryo, as it develops within an incubated egg, has formed a very useful model for understanding the development of vertebrates, especially humans, for over 100 years. Many aspects of development in the chick are very similar to the processes involved in development of the human embryo and foetus. The chick embryo is particularly easy to study because it develops in an egg, which is easy to access by cutting a window in the shell. This allows researchers to follow developmental process es in real time and also to access the embryo to carry out experimental manipulations, in ways that are not possible (or are very challenging) in the mouse model. We have generated transgenic chickens in which all the cells of developing embryos express green fluorescent protein (GFP) and have shown that these embryos can be used in transplantation experiments with many based on the ability to image GFP in live embryos. We have also developed two additional novel fluorescent protein transgenic l ines and propose to generate three more that express fluorescent proteins as reporters for different processes in development. We shall make eggs (embryos) from all these transgenic lines available to the research community.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.3 CHEMICAL AND PHYSICAL SCIENCES
Health categories: GENERIC HEALTH RELEVANCE
Title: Palmitoylation-Dependent Endosomal Cycling of SNAP25: Mechanisms and Functional Relevance.
Funder: Wellcome Trust

Abstract: Cells contain distinct organelles that perform defined and essential cellular functions. Therefore, a critical feature of cells is the ability to target proteins to specific organelles where their function is required. Intracellular protein targeting is mediated by transport vesicles, which move towards and fuse with a specific organelle, delivering their protein cargo to this location. Similar vesicle fusion events underlie secretion of molecules such as hormones, and the uptake of essential nu trients. Defects in these membrane fusion pathways are associated with many debilitating conditions, such as diabetes. Because of its obvious importance, there is considerable interest in identifying and characterising proteins that regulate membrane fusion. This project will examine a protein called SNAP25, which regulates membrane fusion at two distinct intracellular locations. Intricate mechanisms are required to target SNAP25 to these different locations, and this project will test the hypot hesis that the addition of lipids to SNAP25 is a key regulatory mechanism controlling its localisation and therefore setting the operational efficiency of different intracellular membrane fusion pathways. Understanding how lipidation regulates SNAP25 localisation and function has additional significance due to the ability of specific drugs to interfere with this process, thus offering potential to modulate intracellular membrane fusion pathways.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Expansion of Confocal Laser Scanning Microscopy.
Funder: Wellcome Trust

Abstract: Fluorescence microscopy is a vital tool in understanding how cells and organs work. This application sets out our need for high-resolution three-dimensional (3D) images that illustrate architectural features of fixed or slowly moving live samples, and also our requirement for recording the dynamic processes that occur in live cells, from which significant quantitative data are extracted. These apparently opposing requirements have previously required two different types of system. This proposal requests funding for a single technological platform, confocal laser scanning microscopy, that will provide a powerful tool for ongoing studies advancing our knowledge of cardiovascular, reproductive, haematological and immune system function in health and disease.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Structural analysis of Wntch signalling in Drosophila.
Funder: Wellcome Trust

Abstract: The ability of cells to communicate with each other is an essential element in the construction of organisms and the maintenance of their tissues and organs. These functions are mediated by a sophisticated set of molecular devices that emit and receive chemical signals. We call these signal transduction pathways and the last few years have seen significant developments in the description of their structure and interactions. However, our current view of these pathways is not integrated in the s tructure and function of the cell. Diagrams are easily found that link components of these pathways with each other and draw vectors between the cell surface and the nucleus but ignore the obvious fact that these relationships are built upon and use the structural components of cells. We want to study the integration of signalling with the machinery of the cell by focusing on a signal receptor, Notch, and the way it interacts with an intracellular functional network, the trafficking machinery, w hose role is to organize and sort the components of the cell. These studies will not only increase our understanding of the signalling event but are likely to yield new targets for biomedical research.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: RNA functional profiling by gene deletion in a model organism.
Funder: Wellcome Trust

Abstract: Basic biological processes in human cells are similar in simple organisms like yeast allowing scientists to apply what they learn in yeast to human cells. The first cell to have its genome sequenced was the yeast cell, allowing resource development for yeast research. One resource is the deletion of almost all genes that make the proteins of yeast cells. Gene deletions are valuable as they can be used to investigate the function of genes and how cells react to drugs. While deletion of genes that make proteins can be informative, proteins are not the only molecules within cells that carry out biological processes. RNA is another molecule that plays an essential role in cells. Therefore, by investigating only protein deletions scientists only see part of how cells work. Individual yeast strains will be constructed where genes that make RNA are deleted. By deleting RNA genes we will determine the functional consequence to the cell of not having that gene. RNA deletion strains can be combi ned with protein deletion strains to allow investigation of the complete set of molecules important for cell function. Finally, RNA deletion strains will be stored to provide a lasting resource freely available to all scientists.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Mechanisms of RNA turnover and processing.
Funder: Wellcome Trust

Abstract: Cells contain complex mixtures of macromolecules that often function in large assemblies, in which the many different components function collectively as macromolecular machines . Some of these complexes have important regulatory roles. The aim of this project is to understand how macromolecular machines function in the cell in the control of the expression of genetic information. Part of this control is mediated by machinery that affects the lifetime of the information. In bacteria, some compo nents of this machinery appear to be required for the organism to survive and, in certain pathogenic bacteria, to cause damaging infections. The project is aimed at addressing the basic question of how such assemblies work, and whether they might enable communication between different processes in the cell to help coordinate complex activities. The detailed information could prove useful in the design of new compounds that counter bacterial infection or improve the efficiency of chemotherapeutic agents.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Regulatory Mechanisms in Myosins.
Funder: Wellcome Trust

Abstract: Many of our bodily functions depend on the activity of tiny motors that are single molecules of protein called myosins. These act as transporters inside cells and also generate force, as in muscles. Myosins have become diversified to fulfil different roles in the body, so there are 39 myosin heavy chain genes in the human genome, each used for specific tasks. To avoid chaotic traffic jams, the activities of myosins are carefully controlled but we currently know little about how this is achieved. Our recent research indicates that when myosins are not needed they are folded up into an inert, compact form that is quite different from the extended and flexible active myosin. We will use powerful electron microscopes to work out the 3D structures of several different types of myosin in this compact form by recording and analysing thousands of images of individual molecules. We will also identify the binding of myosins to other proteins that switch them on, using both the electron microscop e and in living cells. The results will give us clues about how cells regulate the myriad other processes that keep them alive, and also help in designing therapies for people with malfunctioning myosins.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Structural Molecular Biology Infrastructure for the Astbury Centre at Leeds.
Funder: Wellcome Trust

Abstract: In order to develop new medicines and treatments for diseases, it is essential to understand the roles played in both health and disease by biological molecules such as protein, DNA and RNA in the cells of the body. Structural biology is a vital tool that enables us to visualise directly the three-dimensional arrangement of atoms in these molecules, thus providing detailed insights into their function and misfunction. Since the first structures of DNA and proteins were determined in the 1950s, s tructural biology has had a huge impact on our understanding of the fundamental processes of life, and has led to the development of better treatments for disease. The Astbury Centre at the University of Leeds is a leading UK research centre dedicated to using these methods to understand living processes. We are requesting support for new instrumentation for the three major structural biology methods: X-ray crystallography, electron microscopy and nuclear magnetic resonance spectroscopy, that to gether allow us to probe molecular structure, dynamics and assembly. We will also purchase two instruments used to characterise samples before structural studies to ensure that they are in a biologically relevant state.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Upgrade of NMR Spectrometer Consoles to Secure the Future Operation of the Biomolecular NMR Facility in the Department of Biochemistry, University of Cambridge.
Funder: Wellcome Trust

Abstract: A substantial aim of our work is to investigate the properties of proteins and their interactions at atomic resolution using nuclear magnetic resonance (NMR) spectroscopy. We currently operate a highly successful multi-user Biomolecular NMR Facility in the Department of Biochemistry (University of Cambridge) and are requesting funds for an upgrade of the ageing electronic equipment to secure the future operation of the research facility. Nuclear magnetic resonance (NMR), like its cousin MRI, is a non-invasive technique for investigating structures. In contrast to MRI, which is employed to look at organs and tissues, NMR is used to look at the structures of molecules, in our case at proteins and nucleic acids such as DNA and to identify how these molecules work together. Knowledge of these molecular structures and interactions enables us to understand how the molecules function within the body and how they can go wrong ultimately leading to dysfunction associated with many different ill nesses. The understanding at such a molecular level is essential to develop strategies how to fight a multitude of diseases.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE