NIHRDataInsights/HRCSData huggingface dataset:
Title: MAPK-signalling in development and disease
Funder: Medical Research Council

Abstract: Melanoma is the most deadly form of skin cancer, resulting in the premature death of almost 2000 people each year in the UK alone. Early detection is essential, as melanoma is notorious for being resistant to most therapies. One of the ways in which melanoma can develop is from moles (nevi): highly common and benign tumours of melanocytes, prevented from becoming neoplastic by activation of senescence. Senescence is a stable state in which cells are prevented from dividing. While a normal cell reaches senescence as it ages, it is now understood to act as a protective mechanism against cancer as well. Thus, understanding the mechanism whereby cells can sense early cancer events, and then initiate senescence, is of critical importance for our understanding of melanoma - and all cancer development - and in the design of future therapies. Our work has two main themes, MAPK-signalling in cancer and development: CANCER We have developed a mole-to-melanoma zebrafish model of cancer progression based on the most frequently mutated human gene in melanoma, BRAF. Significantly, with the loss of p53, a major regulator of senescence, melanoma rapidly develops. Because of the highly similar genetic and cancer pathology between humans and fish, we view the BRAF expressing fish as the primed human condition - a unique starting point for identifying novel genes, environmental conditions, and therapeutic compounds that control senescence and the mole-to-melanoma transition. Our aims are to: define and genetically test the role of senescence in melanoma progression; explore the gene-environment interface of UV-induced melanoma progression; test for the genetic role of new melanoma driver mutations in promoting and maintaining melanoma; screen small-molecule libraries to identify molecules that disrupt melanocyte development, movement and pigmentation, and directly test these in our animal models of melanoma. DEVELOPMENT Recently, the perception of the RAS-BRAF-MEK-ERK signalling pathway genes as cancer-genes has been dramatically altered by the discovery that, in people, germ-line mutations in RAS cause Costello syndrome, and mutations in BRAF and MEK are the cause of cardio-facial-cutaneous (CFC) syndrome. We are using the zebrafish system to understand the normal developmental function of BRAF, MEK1 and MEK2; the phenotypes imposed by CFC BRAF and MEK alleles; and to test the effects of chemical inhibitors on the activity of the CFC alleles. In this way, we strive to gain insight into how BRAF signalling contributes to the complex three-dimensional development of the embryo. Importantly, our early data suggests that small-molecule inhibitors designed to treat cancer development, can also restore normal development in CFC-model embryos. CFC in people is a progressive disease, and this works allows us to explore a new avenue using known cancer drugs to aid developmental syndromes.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;SKIN
Title: An integrated platform to assay melanoblast and melanoma invasion of epidermis in vitro
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: Mathematical and computational modelling are powerful techniques that allow the testing of hypotheses in silico before actual experiments are conducted. We are currently using these techniques to replace the use of animals in our own research into neural crest stem cells (NCSCs). Melanoblasts are a NCSC subtype that populate the embryonic epidermis and become the pigment producing melanocytes found in skin and hair follicles. Defects in their development lead to pigmentary disorders whilst reactivation of their developmental program causes metastatic melanoma. Recent advances in imaging technologies have allowed melanoblasts to be studied using time-lapse confocal microscopy and for melanoma metastasis to be investigated using intra-vital imaging. These methodologies are powerful and informative but the burden on animal resources is high, especially where complicated genetic crosses are required. This project is designed to develop an in vitro system to assay melanoblast behaviour and melanoma cell metastasis in an epidermal organ substitute using live-imaging, image analysis and mathematical modelling. We will genetically engineer keratinocyte cell lines which can then be differentiated into epidermis and used as an environment in which to assay the behaviour of primary melanoblasts and melanocyte/melanoma cell lines. In parallel we will use mathematical modelling of NCSC behaviour and the key signalling pathways that modulate this behaviour to refine and explore our in vitro system. Our approach will reduce the number of animals required to study melanoblast development as well as establishing a tractable easily manipulated model system. By altering the host-tissue's genetic background in vitro and by choosing NCSC lines derived from different genetic backgrounds, complex genetic experiments can be conducted with great flexibility and without the need for a large mouse breeding program. Furthermore the use of live-imaging and careful mathematical modelling and prediction to refine our experimental approach will allow us to develop an efficient pipeline for pathway analysis further reducing animal usage.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: CANCER AND NEOPLASMS;SKIN
Title: Labelled IMS TAG Proteins for Quantitative Mass Spectrometry Imaging
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: MALDI-MS Imaging is a novel label free imaging technique that can be used to image the changes in multiple protein responses following treatment. We have previously applied MALDI-MS imaging to the study of;ex-vivo human skin,3D cellular skin models as well as human tumours, xenografts and allogenic animal tumour models. One of the major challenges facing MALDI-MS imaging is the quantification of changes in protein response observed in the images. To date, whilst progress has been made in quantitative analysis of small molecules by MALDI-MS imaging quantitative analysis of protein images has not been attempted. We have recently introduced the concept of "IMS-TAG" proteins for validation of protein identity. "IMS-TAG" proteins are recombinant proteins produced to contain signature peptides from a variety of proteins of interest that are present in the tissue under study. These peptides are released by enzymatic digestion of the recombinant protein and are used as positive controls for matching accurate mass, ms/ms spectra and ion mobility drift times in imaging experiments. Here it is proposed to further develop the IMS-TAG idea by producing two 15N labelled IMS-TAG proteins: one containing signature peptides for clinically relevant skin proteins involved in psoriasis and eczema and one containig peptides for those proteins involved in cancer progressions. The enzymatically generated labelled peptides will then be used as internal standards for quantitative MALDI-MS imaging experiments by incorporation of the unlabelled protein into tissue homogenates to create calibration standard arrays and by subsequently spraying cut sections of the homogenate arrays with labelled protein as an internal standard. Although this study is being carried out on skin and tumour models the methodology would be directly applicable to all other tissues. Software for the extraction of quantitative information will be developed in collaboration with Waters Corp.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS;SKIN
Title: Integrative genomic profiling of inherited cutaneous tumours .
Funder: Wellcome Trust

Abstract: Patients who inherit a single defective gene that is important in hair formation can develop multiple disfiguring skin tumours at hair bearing sites. By using tumour tissue from these patients obtained during surgery to control tumour burden, I intend to explore altered growth signals that cause these tumours to develop. By using two different genetic conditions that develop similar tumour types, I plan to perform detailed molecular analysis to look for signals that may explain the similar patte rns of tumour growth seen. In particular, I am interested in how a protein that has been shown to be critical in the development of these tumours seen in both conditions in mice, called GLI, may be working in different ways in the different genetic conditions. GLI is an important protein in human development and cancer. By determining which survival signals that GLI may activate in each of these conditions, I intend to gain further understanding around this important protein. This information wo uld be offer insight into the mechanisms and hence treatment of both these rare tumour conditions as well as sporadic tumour conditions. Furthermore the mechanisms found to be altered by GLI bears relevance to mammalian biology.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;SKIN
Title: Creating high fidelity digital tissue substrates for the development of non-invasive microstructural MRI
Funder: Medical Research Council

Abstract: Diffusion-weighted MRI (DW-MRI) is a technique used to aid in the clinical diagnosis of cancer and ischemic stroke. Recent application of microstructural tissue models to DW-MR signals has enabled quantitative assessment of tissue parameters e.g. cell size or vascular volume, and has been applied in clinical feasibility studies. Digital tissue substrates (DTS) have been central to the development of microstructural MRI. Synthetic DW-MR signals can be simulated from a DTSs and microstructural parameters extracted. The DTSs then provide a ground truth to evaluate the extracted parameters. As DTSs can be easily manipulated, they provide an ideal tool for systematically investigating how DW contrast is dependent on tissue geometry; and for developing new methods of DW-MR signal quantification, such as machine learning. Current DTSs consist of collections of spheres and cylinders to represent cells and vessels respectively. There is growing realisation in the field that these simple geometries may not capture key changes in tissue microstructure associated with certain pathologies; and cannot provide adequate validation. Recent advances in three-dimensional optical imaging provide a unique opportunity to create empirically-derived DTSs with much greater scale, complexity and realism than has previously been achieved. These optical imaging techniques (optical projection tomography (OPT) and high-resolution episcopic microscopy (HREM)) can generate image data from large tissue volumes (~2cm3) at sub cellular resolution (typically ~1um). In this fellowship, I will create a library of DTSs using 3D optical imaging data and a 3-dimensional cellular Potts modelling platform. To create such a library, I will extract the morphometric parameters from 3D imaging data using machine learning segmentation. These parameter spaces will then be used to parameterise the computational model, which can then generate DTSs within a particular parameter space.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS;STROKE
Title: Interactions between cancer and stroke:A national electronic data linkage study
Funder: Chief Scientist Office, Scotland

Abstract: Both stroke and cancer are common and can have a devastating impact on a person’s life and family. This is much worse if they have both conditions together, raising difficult questions about best treatment and most likely outcome. There is a lack of research investigating the impact of stroke and cancer for people suffering with both but it is a very important area which needs to be researched further. National datasets on cancer, stroke, hospital admissions, economic and social status, medication prescribing, health board performance targets, and death will be linked to create the first extensive and novel research database of patients with both cancer and stroke. We will research: the risk of stroke in cancer patients, the risk of cancer in stroke patients, the effect of a cancer diagnosis on stroke treatment and outcome, and the effect of a stroke diagnosis on how cancer is managed and treated. This project will allow us to recommend personalised treatment and medication plans, based on real life data, for patients suffering from both diseases. This will lead to better informed decisions, improved patient management and a reduced burden on the National Health Service.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: CANCER AND NEOPLASMS;STROKE
Title: Advancing and integrating population and individual approaches to smoking cessation
Funder: Cancer Research UK

Abstract: Background Smoking remains the largest preventable cause of cancer. Accelerating the rate of decline in prevalence is achievable through a sustained scientific effort to build a comprehensive model of smoking cessation. Aims The proposed programme aims to advance and integrate population and individual approaches to smoking cessation by: 1. providing insights into population-wide influences on smoking and smoking cessation 2. advancing the scientific foundation, and further the development of, potentially wide-reach digital technologies. Methods Theme 1: We will substantially extend our major national surveillance programme, the Smoking Toolkit Study (STS), a series of monthly, national, household, face-to-face surveys of the adult population of England, with follow-up by telephone. It includes detailed questions on smoking and smoking cessation, providing population-level estimates of factors influencing quit attempts and quit success. The new programme will continue a 60 further waves (100,000 respondents), and include a validated scale to assess hazardous drinking. There will be enough data for adequately powered studies to understand the population-level effects on quit attempts and quit success of social marketing campaigns, different types of opportunistic GP advice, use of e-cigarettes, and the ‘real-world’ effectiveness of a wide range of stop-smoking aids (including smartphone apps and printed materials) and how these are affected by factors such as social disadvantage and hazardous alcohol use. We will use time series analyses and General Linear Models to estimate parameters in a general model of smoking cessation. Theme 2: We will use our strategic collaboration with the major stop-smoking service provider, Quit 51, to undertake an RCT involving 40,000 smokers comparing different digital stop-smoking aids and a second RCT examining the effect of adding stop-smoking modules to a smartphone app in 4,000 pregnant smokers. We will also use a collaboration with the developer of one of the world’s most popular stop-smoking apps (3000+ new signs ups per day) to develop and test innovative ideas for enhancement. How the research will be used Our close links with public health agencies and service providers means that, as with our existing programme, the findings can be rapidly applied to policy formation and implementation as well as large scale delivery of stop-smoking support. The findings will also support our theoretical understanding of the processes by which human and digital support bring about smoking cessation and behaviour change more broadly which, in turn, will generate more effective interventions.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: CANCER AND NEOPLASMS;STROKE;CARDIOVASCULAR;RESPIRATORY
Title: A therapeutic anti-IL16 antibody for the treatment of Ischaemic Reperfusion Injury
Funder: Innovate UK

Abstract: When there is a sudden loss of blood flow, such as may occur during surgery or as a result of a blood clot, tissue damage can occur. In addition, when blood flow is restored further damage can be caused related to the ensuing inflammatory response and this is referred to as 'Ischaemic Reperfusion Injury'. We have generated an mouse antibody (via immunisation with a human protein) that is able to neutralise the activation and migration of inflammatory cells to sites that have been damaged by loss of blood supply, and thus reduce tissue and organ damage. We have shown that this antibody can successfully prevent acute kidney damage in a mouse model, where blood flow is restricted. We now aim to increase the potency of this mouse antibody and modify it such that it will be safe to use in humans to prevent reperfusion injury occurring during surgical procedures. It is likely that it will also prove to be useful for other inflammatory diseases.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR
Title: Guide Cardiac Resynchronisation Therapy - Guide CRT
Funder: Innovate UK

Abstract: Cardiac Resynchronisation Therapy (CRT) has been shown to be a safe and effective treatment option in patients with advanced drug-refractory Heart Failure (HF), systolic dysfunction and ventricular dyssynchrony. However, up to one-third of patients implanted with a CRT device show no improvement in symptoms and up to half of patients show no improvement in cardiac function. These non-responders are a strong burden to healthcare systems by causing considerable unnecessary costs, e.g. for devices, implantations, recurring follow-up visits as well as hospitalisations for acute HF decompensation The aim of this project is to develop a single platform which integrates all stages of the CRT pipeline, referred to as the “Guide CRT”, to improve response rate. The main components of this include MR clinical imaging protocols dedicated to HF patients, tailored image processing tools (segmentation of the heart morphology, myocardial scar and coronary sinus, as well as analysis of left ventricle (LV) wall motion), fused visualisation for improved patient selection and planning of LV lead placement, and the image-based guidance technologies to support CRT device implantation. Guide CRT will be evaluated on a cohort of 50 patients. Through the proposed joint efforts between leaders in their respective industrial, academic and clinical fields, we aim to demonstrate that integrating comprehensive multimodal imaging data and tools can help to provide answers to the great challenges of CRT, namely identification of patients who are likely to respond and guiding LV lead placement to maximise this reponse.


Research activity codes: 6.4 SURGERY;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: Atherosclerosis stratification using advanced imaging and computer-based models
Funder: Innovate UK

Abstract: The goal of the proposed project is to develop a novel tool for atherosclerosis risk stratification. Cardiovascular disease (CVD) (especially, coronary artery disease and stroke) is the leading single cause of morbidity and mortality in the Western world. Vascular atherosclerotic disease is a causative factor in a high percentage of CVD events. Widely accepted risk markers that allow predicting cardiovascular events such as myocardial infarction and stroke are currently based on risk factors such as smoking, weight and blood pressure. These lifestyle factors and medical conditions are derived from population based studies and are linked to an average probability of having a CV event, but do not measure the individual’s personal risk, and can therefore result in potential overtreatment. The main deliverable from this project will be a tool to assess the grade of atherosclerosis using multi-parametric advanced imaging in combination with biophysical computer models. Advanced imaging will be used for plaque burden measurement and plaque component characterization. In addition, biophysical models will be used to predict biomechanical properties related to atherosclerotic changes in the vascular system. For the first time, different parameters will be integrated into one clinical tool for comprehensive and individual risk stratification on different assessment levels.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: The Combined Catheter: Integrating drug delivery and pressure measurement to improve stratification of therapy in patients with coronary artery disease.
Funder: Innovate UK

Abstract: Integrating drug delivery and pressure measurement to improve stratification of therapy in patients with coronary artery disease. A novel product to be used by cardiologists and cardiac surgeons in the catherterisation laboratory to help them decide whether to implant a stent in patients with symptoms of coronary artery disease or treat them with medicines. The technology will deliver all of the proven benefits of Fractional Flow Reserve measurement, whilst making the procedure more efficient and easier to perform. By adopting this integrated approach, the NHS can will significantly improve patient experience and quality of life at the same time as achieving financial savings of £20 million each year.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: Unravelling the mechanisms of vascular protection by omega-3 PUFAs to optimise and support their use as bioactives by the food industry
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Diet is an important factor in the risk of cardiovascular disease (CVD), and this has led to enormous interest in bioactives, food components which provide medical or health benefits, and how they may be exploited to produce healthier foods. This multi- and interdisciplinary collaborative project will investigate the mechanistic basis of the beneficial actions of omega-3 polyunsaturated fatty acids (PUFA), widely marketed as bioactives, on vascular health. CVD is characterised by inflammatory processes which begin with dysfunction of the vascular endothelium and increased migration of monocytes into the intima followed by the formation of macrophage foam cells. We have already shown that chylomicron remnants (CMR), the lipoprotein carriers of dietary lipids in the blood, directly influence endothelial cell (EC), monocyte and macrophage functions and that these effects are influenced by the type of fatty acids carried. This project will test the emerging hypothesis that in the postprandial phase omega-3 PUFA carried in CMR modulate the molecular events that promote vascular wall dysfunction by reducing the detrimental effects of the particles on ECs, monocyes and EC:monocyte interaction. This may occur by: suppressing pro-inflammatory/-oxidant signalling events regulating inflammatory gene expression; altering the balance of mediator release; and activating cytoprotective pathways. These studies will be complemented by parallel investigations of the cellular effects of particles isolated from fed humans, and of the effects of omega-3 PUFA-enriched CMRs on the molecular phenotype of vascular cells using bioinformatics. This project will provide highly novel insight into the molecular control of vascular cell function by omega-3 PUFA carried in CMRs in the postprandial phase. Understanding how dietary intake of omega-3 PUFA affects vascular health will allow the food industry to accurately promote their health benefits and underpin endeavours to develop healthy foods.


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: CARDIOVASCULAR