NIHRDataInsights/HRCSData huggingface dataset:
Title: Establishing the Role of the FoxG1 transcription factor in normal and glioma-derived neural stem cells.
Funder: Wellcome Trust

Abstract: Glioblastoma (GBM) is the most common and lethal primary brain tumour. GBMs contain a population of cells that display characteristics of neural stem cells. Understanding the action of the lineage specific transcription factors responsible for orchestrating self-renewal in this population and in their normal stem counterparts offers promise in identifying therapeutic targets. Through pilot studies comparing gene expression in normal NS cell cultures with GBM-derived NS (GNS) cells we have ident ified FOXG1 as a brain-specific transcription factor that is consistently overexpressed in GNS cells. Previous studies have implicated FOXG1 in control of cell cycle and differentiation pathways (p21 and Bmi-1). The aim of this project is to define the function and transcriptional targets of FOXG1 in these malignant and non-malignant contexts. I will make use of established and well characterised NS and GNS cell lines as the model system and use intracranial xenotransplantation as an in vivo a ssay of tumour formation. The objectives are: 1) Monitor the changes in FOXG1 mRNA and protein during differentiation. 2) Perform gain-of-function studies using 'tuneable' overexpression. 3) Perform loss-of -function studies using the latest genome editing technologies (TALENs). 4) Define genome-wide transcriptional targets of FOXG1 using chromatin immunoprecipitation and deep sequencing (ChIP-Seq).


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;CANCER AND NEOPLASMS
Title: From the ectoderm to the synapse: Structural and functional characterisation of protein-protein interactions in neural development.
Funder: Wellcome Trust

Abstract: Neural development is a continuous process that is crucial for proper organismal function. A spectrum exists, beginning in the gastrula-stage embryoand culminating in innervated synaptic junctions throughout the entire body[1]. BMP gradients exist within developing embryos, controlled by antagonists such as Coco, Cerberus and BAMBI. This mode of BMP antagonism defines the embryo's dorsal ectoderm as the source of progenitor cells for an entire nervous system[2,3,4]. Synaptic contacts must be established, a non-cell autonomous process. This entails cell adhesion complexes, such as the RPTP?:TrkC interaction[5]. Complexity is added by TrkC's physiological ligand, NT3, which we hypothesise contributes to a novel hexameric activity-dependent synaptogenic complex. Besides developmental functions, these proteins display roles in metastatic cancers, as well as offering potential therapeutic options for neurodegenerative disease[6,7]. The aim of this project is to characterise the extracellular interactions in both systems. This will include biophysical analysis - we aim to solve crystalstructures of protein complexes from both systems to better understand the extracellular cues at hand. Cell-based analysis will also be undertaken, to further characterise interactions and dissect downstream signalling implications. Better understanding of such interactions will greatly reinforceour understanding of the roles of these proteins in development and disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;CANCER AND NEOPLASMS
Title: Understanding Signalling Pathways Mutated in Inherited Disorders
Funder: Medical Research Council

Abstract: My laboratory focuses on unravelling the roles played by protein phosphorylation and ubiquitylation pathway components that emerge from the genetic analysis of human disease. In the current quinquennium the attention will be based on dissecting signalling pathways associated with Parkinson’s Disease (LRRK2), cancer (SGK3 pathway) and hypertension (WNK pathway). The aim of our research is to focus om mechanism and understand how the signalling components that we are studying are regulated and function. How mutations in these pathways disrupts biology to cause disease is also a major question. We hope to harness this information to elaborate a better understanding of human disease and to develop improved strategies to better treat and diagnose malady. For the LRRK2 research the key aims of this work are: 1. Do mutations in “Parkinson’s genes” promote LRRK2 activity and Rab protein phosphorylation? 2. Are there any specific stimuli that induce activation of LRRK2 and phosphorylation of Rab proteins? 3. How does LRRK2 mediated phosphorylation of Rab GTPases affect downstream biology? 4. Generation and use of monoclonal antibodies to better detect endogenous phosphorylation of Rab proteins by LRRK2. In parallel to this research we are working with clinicians and pharmaceutical companies with an interest in testing the therapeutic benefit of LRRK2 inhibitors for the treatment of Parkinson’s. For the SGK3 project the work will focus on studying the regulation and function of SGK3 in caner. The aims are: 1. Obtain a better understanding SGK3 biology-identification of novel SGK3 substrates in breast cancer cells; 2. How is SGK3 activated by Growth Factors. This work will help define whether SGK3 inhibitors will have therapeutic benefit for cancer. The WNK project concerns understanding how the WNK kinases that control blood pressure are regulated. This project could provide fundamental information of how cells sense and respond to osmotic and ionic stress, cellular processes that are very poorly understood.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;CANCER AND NEOPLASMS;CARDIOVASCULAR
Title: MICA: [18F]LW223: a superior TSPO PET radiotracer for a clinical breakthrough to detect regional tissue inflammation
Funder: Medical Research Council

Abstract: Inflammation plays a critical role in the development, progression and clinical outcomes for a number of human diseases, including highly prevalent cardiovascular, neurological and oncological diseases. Despite this central role, clinical biomarkers for quantification of regional tissue inflammation in vivo and non-invasively with high sensitivity and specificity are not available. In this project, we propose to address this clinical need by developing a new imaging biomarker with potential to transform clinical diagnosis, management of a plethora of human diseases, drug development and treatment of multiple diseases. Our new imaging biomarker targets the 18kDa translocator protein (TSPO), a biological target abundantly proven to measure inflammation in pathologies throughout the body, and makes use of Positron Emission Tomography (PET) technology as an approach to achieve greatest sensitivity and specificity for detection of inflammation. Our new imaging biomarker, [18F]LW223, aims to address bottlenecks associated with current and long-standing TSPO PET technology: (1) the inability to scan the whole-human population due to sensitivity toward the rs6971 genetic polymorphism; (2) the lack of clinical universalism due to complex imaging protocols that are only possible in a limited number of highly specialised PET centres worldwide; and (3) the difficult market commercialisation due to labelling with short-lived radioisotopes. This project will conduct first in human studies with [18F]LW223 and will explore its utility as a biomarker of regional tissue inflammation in humans versus other clinically used metrics in the national health service. If successful, results from this study will catapult the use of quantitative TSPO PET in many diseases in humans and model organisms worldwide.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL;CANCER AND NEOPLASMS;CARDIOVASCULAR
Title: Genome Damage and Stability Centre
Funder: Medical Research Council

Abstract: Cellular DNA is continually damaged, both endogenously (e.g. by hydrolysis, oxidation, methylation) and from exposure to exogenous agents (e.g. solar UV, ionising radiation, chemical carcinogens). Complex arrays of DNA damage response (DDR) pathways counteract the deleterious effects of such damage. In the past quinquennium we have established the GDSC as a unique grouping of scientists linking basic research on DDR pathways to human disease. We have also established links with the new medical school (Brighton and Sussex Medical School) and helped formulate the host institute?s vision for translational medicine. Our strength in basic science is internationally recognised and supported by our publication and grant award record. In the next quinquennium, we aim to develop our basic research in DDR pathways to include links to translation and to initiate new training programs aimed at integrating clinical approaches with our science. Specifically, to promote training we propose to establish a 1+3 PhD program in Imaging Science and to offer five 1 year clinical fellowships to give experience of laboratory science to junior clinicians. To promote translational research links with the medical school and the local NHS Trust, we propose to establish a cancer tissue bank and set up mouse xenograft models. Finally, we propose to strengthen our basic science by introducing state-of-the-art methodologies within the grouping for Surface Plasmon Resonance (SPR), fluorescence microscopy and combined Total Internal Reflection Fluorescence and Atomic Force Microscopy (TIRF/AFM). Our plans for the next quinquennium are integrated with the host institute?s vision for translational research. This vision aims to provide a pipeline from basic laboratory science through medicinal chemistry/clinical pharmacology to early stage clinical trials. Cancer is one of the three research themes around which the medical school was based and which underpin the translational vision (the others being neuroscience and immunology/infection). Recent investments have established the Clinical Sciences Imaging Centre (CSIC) with both fMRI and 64-Slice-PET-CT and the Clinical Investigation & Research Unit (CIRU), a fully staffed phase I/II unit on the hospital campus. The GDSC proposes to provide the basic science for the cancer theme. We intend to use the next quinquennium to further strengthen our international profile in basic science and to promote meaningful crossing points between basic and clinical scientists through joint training, shared methodology and specific resource development.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: NEUROLOGICAL;CANCER AND NEOPLASMS;INFECTION
Title: Developing statistical methodology in longitudinal modelling of biomarkers
Funder: Medical Research Council

Abstract: Aim To develop longitudinal statistical methods for disease prediction in individuals, which are accessible to applied statisticians and epidemiologists. Objectives 1. To develop, evaluate and apply statistical methods that allow for complex within individual correlation structures, non-ignorable dropout, left censoring of measurements, non-linear trends and temporal changes in correlation between multiple biomarker trends. 2. To generate guidelines for conducting analyses, and produce accessible software implementing the developed methods that can be used by applied statisticians and epidemiologists. Methodology The proposal concerns the development of statistical methods to model one or more biomarkers whilst accounting for the issues stated in objective 1 that can complicate longitudinal analysis. The inclusion of non-stationary stochastic random terms, such as the integrated Ornstein-Uhlenbeck process will be used to model the within-individual correlation structure. Joint modelling of the longitudinal data and one or more dropout processes will account for informative dropout. Maximum likelihood methods will be used to analyse linear mixed models with left censoring. Non-linear trends in one or more biomarkers will be modelled by fractional polynomials. All developed methods will be applied to datasets collected on patients with progressive diseases: HIV, prostate cancer and multiple sclerosis. Developed methods will be implemented as freely available routines in widely used statistical packages Stata and R. Scientific/medical opportunities The developed methods will be used to answer important clinical research questions of disease prediction in individuals in three medical research areas. The provision of methods, guidelines and software for use by applied statisticians and epidemiologists will also result in clinical advancement in other areas too.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: NEUROLOGICAL;CANCER AND NEOPLASMS;INFECTION
Title: Genetic improvement of wheat to reduce the potential for acrylamide formation during processing.
Funder: Biotechnology and Biological Sciences Research Council

Abstract: This LINK project involves groups from Rothamsted Research, the John Innes Centre and wheat supply chain businesses. It addresses the formation of the contaminant, acrylamide, during high-temperature cooking and processing of foods. Cereals generate half of dietary acrylamide. The European Commission is about to issue guidance values on acrylamide levels in food and the current draft proposes levels that will not be achievable for many products. Methods for reducing acrylamide formation during processing are difficult to apply to wheat. Attention has therefore turned to the raw material, wheat grain. The thermal degradation of free asparagine in the presence of reducing sugars during the Maillard reaction is the major route for acrylamide formation and the limiting factor in wheat is free asparagine. This project will identify genotypes of wheat with 'high' and 'low' acrylamide-producing potential. The site for synthesis of the free asparagine that accumulates in wheat grain under normal and stress conditions will be identified. Metabolite and gene expression profiles will be obtained to compare a low asparagine DH line, SR3, with one of its parents, variety Spark; these genotypes differ in grain asparagine concentration by 40 %. This will identify the enzymes and genes that determine free asparagine concentration in wheat grain. QTL for free asparagine concentration that are being identified within a current PhD project (ends 2010) will be narrowed. Genetic markers for low free asparagine concentration will be identified. Targeted mutagenesis and genetic modification will be used to change the activity of key enzymes and produce very low asparagine genotypes. The impact of reductions in grain asparagine on performance in industrial processes will be assessed by industrial partners. The programme builds on substantial previous work and will be facilitated by the availability of mapping and TILLING populations, and support provided by industrial partners.


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: NEUROLOGICAL;CANCER AND NEOPLASMS;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Wireless Intracranial Pressure Monitoring System
Funder: Innovate UK

Abstract: ICP measurement and monitoring is an extremely important part of the neurosurgical care for both acute events such as traumatic brain injury (TBI), stroke and cancer patients as well as chronic diseases such as hydrocephalus or benign intracranial hypertension. Current ICP monitoring systems involve a surgical procedure - introducing an intracranial probe through the skin and skull while the external end is connected to a monitor. The benefits of this analogue system are offset by the significant risks of serious, potentially life-threatening, infection of the brain, particularly when the ICP recording is prolonged. It necessitates restricting mobility, particularly difficult for children and elderly patients - two groups commonly requiring prolonged ICP monitoring. Wireless ICP systems remove the infection path. Raumedic Neurovent-P and Christoph Miethke Sensor Reservoir, offer wireless continuous ICP monitoring but use bulky sensors and external readers of high prices that limit their applications. After 12 years R&D at Imperial College, the team has developed a portable platform technology suitable for ICP monitoring, consisting of an implantable miniature wireless sensor, a battery-powered electronic reader and a small flexible external patch antenna. The currently unmet patient needs and excellent system performance encouraged the team to commercialise the product for the benefit of patients and health care systems. The implantable sensor is made from highly stable crystal quartz and other biocompatible materials used in implants for many years. The sensor is equipped with a thin antenna with minimal risk of complication and works in a licence-free band available in Europe, USA, China and most countries. The unique combination of the technologies allows for small and low profle implant as well as reader antennas. The reader is light weight (120g), battery powered and designed for 12 hours continuous ICP monitoring on a single charge. It is equipped with Bluetooth and GSM wireless interface for data transmission to smart devices as well as healthcare servers. It is also equipped with visual feedback (LED lights) for optimal positioning of the external antenna. A recording regime can changed remotely by the clinical team. The interrogator hardware and flexible external antenna are ready for use. The project will cover the complete sensor production process, interrogator software modification, conducting animal trial and preparing for the first human clinical trial. Parallel processes will obtain patient input for system ergonomic assessment and level of engagement with the available data and clinical user requirements for defining data presentation and usage.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL;CANCER AND NEOPLASMS;STROKE
Title: Regulation of iron homeostasis by beta-amyloid precursor protein in health and disease.
Funder: Alzheimer's Research UK

Abstract: Iron is essential for the normal function of the body but when this metal is not guarded it can be converted to a potentially harmful product. The balance between disposing of and retaining iron is fundamental for keeping a healthy cell. The ageing brain and circulatory system are particularly vulnerable as are patients with a broad range of disorders, including Alzheimer’s and cardiovascular disease. The main role of a ‘ferroxidase’ is to convert any potentially harmful iron into a less hazardous form. ‘beta-amyloid precursor protein’ (APP), has a role in this iron balance. Of the 3 main APP forms, the smallest is a ‘ferroxidase’ whereas increasing the size varies its effectiveness. Proposed research will determine if the balance between APP form length, or other known changes, are able to alter iron content in health and disease models. Prospective outcomes will strengthen our understanding on iron balance within the body and provide an explanation for increased iron accumulation in age-related diseases. There is currently no effective therapeutic for these diseases as current treatments only provide temporary alleviation. Increased understanding of the molecular and cellular mechanisms underlying these diseases will lead to better drug design in the future.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;CARDIOVASCULAR
Title: Assessing the Impact of Calcium Channel Blockers on COGnitive function in the very elderly (AI-COG)
Funder: Department of Health (England)

Abstract: Objectives: To investigate impact of a blood pressure lowering drug, a calcium channel blocker(CCB) on cognitive function in those aged >=80 years. Hypothesis: that CCB use will be associated with less cognitive decline. Design:The project includes a systematic review of the scientific literature, collection and analyses of data on CCB use and cognitive function change in people >=80 years. Expected outcomes: Understanding the risk/benefit of CCB use on cognitive function in older adults. Anticipated benefits to the ongoing improvement of health or social care:Immediate benefit includes informing prescribing and either supporting current guidelines or building foundations for a definitive clinical trial.


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION;6.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL;CARDIOVASCULAR
Title: Quantifying vascular influences on neurovascular coupling with fMRI.
Funder: Wellcome Trust

Abstract: Neuroimaging is a research area that uses scanners to investigate the workings of the brain. FMRI is one technique that measures changes in blood flow related to brain activity. When brain nerves (neurons) are stimulated, they consume oxygen which causes blood flow changes nearby. This can be used to determine which areas of the brain perform which functions. However, normal ageing can cause blood vessels to stiffen. This alters the vessels response by causing signal differences that are unrela ted to brain activity. Interpreting results can be difficult since we can t tell if signal differences originate from neurons or from vessels. At Cardiff University, I plan to develop techniques that will correct for vessel stiffening caused by age. In both young and elderly people, I will examine blood flow which is affected by blood pressure and carbon dioxide (CO2) levels. By altering inhaled CO2 levels and measuring blood pressure, I will develop rules that correct for the changes in vessel response caused by ageing. This will advance fMRI by removing vessel differences between groups, thus producing more accurate and reliable findings in studies of healthy brains and those affected by normal ageing and disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL;CARDIOVASCULAR
Title: Looking beyond the mean: what within-person variability can tell us about dementia, cardiovascular disease and cystic fibrosis
Funder: Medical Research Council

Abstract: The aim of this programme is to improve understanding of the role played by within-individual variability around mean trajectories of longitudinal outcomes in three key disease areas: cardiovascular disease, dementia and ageing, and cystic fibrosis. We use multi-outcome models with a mixed-effects location scale sub-model for longitudinal trajectories and a time-to-event sub-model for disease outcomes. We will initially review existing methods and software for modelling within-individual variability and evaluate the performance of these methods using simulation studies. We will then develop new methodologies motivated by current clinical and epidemiological questions in our three key disease areas, including models for dealing with multiple longitudinal outcomes, models using standard Gaussian processes to distinguish between long-term variability, short-term variability and measurement error, change-point models, and multi-state models. Finally, we will embed the new methods into dynamic risk prediction models to allow statistical measures of intraindividual variability to be included as predictors. We will utilise (1) a landmarking approach and (2) a joint modelling approach, which both allow the risk prediction of the probability of some event occurring to be updated dynamically in response to additional longitudinal information. All methodological developments will be accompanied by companion papers in clinical and epidemiological journals. We will make use of existing data resources, including long established cohort studies and registry data. Code with illustrative examples will be disseminated via a dedicated github repository to encourage uptake of our methods.


Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS
Health categories: NEUROLOGICAL;CARDIOVASCULAR;CONGENITAL DISORDERS