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Results

EpiChange: Quantifying longitudinal changes after epilepsy surgery 04 Dec 2017

Resective surgery for epilepsy, where the part of the brain thought to cause seizures is removed, leads to seizure freedom in around 70% of patients 1 year post-surgery. This falls to around 50% at 5 years post-surgery. It is not fully understood why surgery only works initially for some patients, and why this falls over time post-operatively. Surgery has a substantial immediate impact on brain structure, however, the long-term impact of surgery on brain dynamics is poorly understood. In order to make progress in this area we will perform a retrospective analysis of longitudinally acquired electroencephalographic (EEG) data. EEG recordings were made pre-operatively, and post-operatively in 76 patients for up to 5 years. Using univariate and multivariate data analysis, in conjunction with machine learning, we will learn how brain dynamics change after surgery, and if this change relates to outcome. Crucially, we will attempt to identify which factors in brain dynamics correlate with seizure relapse, even years after surgery. If successful, this will pave the way to a larger project where changes can be reverse engineered to give predictions of post-operative decline using pre-operative data. Long-term, this research has implications for other disorders involving longitudinal decline following structural brain damage.

Amount: £99,978
Funder: The Wellcome Trust
Recipient: Newcastle University

Mapping the genetic and cellular basis of human DC haematopoiesis. 15 May 2017

Hypothesis: Human DC haematopoiesis is regulated by specific genetic factors that govern the development of precursors with restricted DC potential, giving rise to peripheral DCs independently of monocytes. Objectives: 1.To identify genes of clinical importance regulating human DC haematopoiesis in vivo. I have shown that DC deficiency syndromes provide a powerful means of analysing the genetic factors that control DC development in vivo. I will further screen and characterise new genetic causes of DC deficiency. 2.To identify human progenitors and precursors with restricted DC potential. DC precursors identified in the mouse have no known human homologues. I aim to solve this problem using transcriptomic profiling to identify and separate precursors with true DC potential from those with monocyte potential (that subsequently form mo-DCs), comparative transcriptomics to discover new cross-species markers of DC precursors and single cell progenitor studies to track monocyte- independent DC potential. 3.To define the intrinsic effects of genetic mutation on discrete stages of DC development. I will use CD34+ progenitors or induced progenitor stem cells from patients with DC deficiency to determine how genetic mutation interrupts discrete stages in DC development, thus integrating the genetic and cellular maps of DC homeostasis.

Amount: £216,055
Funder: The Wellcome Trust
Recipient: Newcastle University

The entropy of behaviour under stress 31 Jan 2017

Stress is both widespread and difficult to detect, with massive health and economic impact on both humans and the millions of animals we care for. Individual differences in response to stressors show behaviour can become more repetitive and stereotypic or more unpredictable and chaotic, so universal behavioural indicators of stress have been elusive. We propose that entropy, a key concept in information theory which captures how chaotic or disordered a sequence of data is, will be a useful approach to apply to behavioural signals, with stress causing extremes in entropy on either side of the spectrum. We propose to test this theory by:   (i)            Developing methods to extract measures of behavioural entropy from automatically collected accelerometer signals;  (ii)           Studying the change in behavioural entropy under acute stress, with individuals selected to provide a variety of response valences;  (iii)          Investigating the effects of individual behavioural differences and personality as predictors of the directional change in entropy.  The overall aim of this research will be to develop a robust and versatile behavioural indicator of stress, with far-reaching applications to understand the neurological changes stress causes, and improve detection of poor animal welfare.

Amount: £0
Funder: The Wellcome Trust
Recipient: Newcastle University

‘Biofuels’ and respiratory health – the potentials of the archaeological record 10 Nov 2016

In the light of climate change and the negative environmental consequences of burning fossil-fuels, an increasing focus has been on ‘biofuels’ as sustainable alternatives. However, the use of silica-rich renewables can have detrimental effects on urban air quality and respiratory health. We will explore this tension by applying modern air quality modelling to a long-lived archaeological settlement, where previous research shows a significant shift in fuels over 1000 years, alongside decreasing settlement density. We will address two problems. The first is our understanding of the long term (> lifetime) relationship between ‘biofuel’ burning, settlement density, and respiratory health. The second is the public understanding of the detrimental effects of these fuels, which are, perhaps erroneously, considered ‘cleaner’ than fossil-fuels. There is great potential to explore the role of archaeology, in understanding this relationship over the long-durée, and as a tool for communicating health issues to communities at risk. The nature of the archaeological record enables a long-term perspective which can inform circumstances of use with minimal health risk. The key goals are to establish a network of interdisciplinary collaborators from archaeology, civil engineering and modern environmental health research, and conduct feasibility studies to support an application for a larger award.

Amount: £42,621
Funder: The Wellcome Trust
Recipient: Newcastle University

The impact of patient mutations in Na/phosphate cotransporters to function and trafficking of the protein 31 May 2018

The renal transport system for inorganic phosphate (Pi), SLC34A1, is central to balancing Pi levels in the human body. Mutations in SLC34A1 have been identified in patients with isolated renal phosphate wasting, generalised proximal tubulopathies (renal Fanconi’s syndrome), renal stone formers and patients with nephrocalcinosis. The spectrum of phenotypes observed points to a complex interplay between the nature of the mutation and the genetic background of the patient. Intriguingly, some of the mutations show a dominant phenotype. The aim of this proposal is to investigate the molecular and cellular determinants for the dominant behaviour of certain SLC34A1 mutations. We have identified two patients with mutations in SLC34A1. The first patient carries a heterozygous SLC34A1 mutation Ile456Gln whilst the second is compound heterozygous for Arg512Cys and a deletion of Val91-Ala97. These mutations will be used to perform functional analyses in Xenopus oocytes and epithelial cell lines co-expressing wild-type and mutated transporters. Chimeric wt-mutant constructs will also be generated to exclude differences in intracellular processing of the individual units. Intracellular trafficking will be tested in renal epithelial cell lines using wild-type and mutated transporters with different fluorescent tags followed by confocal microscopy.

Amount: £0
Funder: The Wellcome Trust
Recipient: Newcastle University

Expression profiling of p53 transcriptional target genes as a predictor of cell fate following non-genotoxic activation of p53 by MDM2 inhibitors 31 May 2018

The purpose of the proposed project is to investigate the differences in p53-dependent gene expression between cells that undergo growth inhibition and senescence in response to p53 activation compared with those that undergo apoptosis. These alternative cell fates, which are cell type and context dependent, have important roles in a range of disease states and responses to therapeutic intervention, but the underlying mechanisms are poorly understood. We have identified a panel of cell lines that epitomise these alternative cell fate responses to p53 activation, which we will investigate by using MDM2-p53 binding antagonists to activate p53 directly and specifically, without DNA damage. In addition, we will use agents which demethylate DNA to test whether pro-apoptotic genes can be re-activated in those cell lines in which these genes appear to be silenced. Techniques used to investigate the downstream consequences of p53 activation will include flow cytometry, enzymatic apoptosis and senescence assays, Western immunoblotting and multiplex qRT-PCR gene expression profiling.

Amount: £0
Funder: The Wellcome Trust
Recipient: Newcastle University

Cell envelope synthesis in Gram positive bacteria: mechanisms, regulation and inhibition 28 Nov 2017

Cell wall synthesis is a highly conserved process in bacteria, and crucial as both a target for our best antibiotics and a source of innate immune signals of infection. The wall defines the shape of bacteria but it is sculpted with the help of conserved cytoskeletal proteins, including MreB, FtsZ and DivIVA. The aim of this project is to study the spatial regulation of wall synthesis, especially cylindrical elongation, in the model Gram positive bacterium Bacillus subtilis. Several factors in wall synthesis appear to be redundant and we will attempt to resolve the adaptive basis for this redundancy, as well as solving specific questions on the function of cell elongation factors. In another major lineage of Gram positive bacteria, the Actinobacteria, cell elongation is achieved by a completely different mechanism involving tip growth and branching. Little is known about the evolutionary pathway leading to these contrasting strategies. We have identified and will undertake comparative studies of an unusual group of Firmicutes that appear to exhibit branching tip growth like actinobacteria. The results will not only enrich our understanding of wall synthesis in general but will also provide insights that we hope to exploit in the search for new antibiotics.

Amount: £1,858,759
Funder: The Wellcome Trust
Recipient: Newcastle University

Unraveling genetic causes and risk factors for severe male infertility 28 Nov 2017

This research will significantly advance our molecular and clinical understanding of human spermatogenesis and severe male infertility. We will study the germline genomes of men with selected infertility syndromes as well as large-cohorts of men with non-obstructive azoospermia, aiming to identify pathogenic mutations in novel male infertility genes and non-coding genomic regions, including complex Y chromosomal abnormalities. In addition, we will use innovative flow cytometry and transcriptomics approaches to study normal and abnormal human spermatogenesis. Finally, we will study the consequences of assisted reproductive technologies for the genome of offspring, and look at the preservation of fertility in this offspring. Throughout this research, we will make use of unique material from infertile patients, their parents and their offspring born through ART. This will allow us study the role of de novo germline as well as somatic mutations as unappreciated causes of severe male infertility. The results of this research will be used to develop novel diagnostic procedures and improve the diagnostic yield in this largely unexplained patient cohort. In addition, this research will provide crucial biological information for the development of novel fertility procedures and provide improved methods to monitor the safety of these procedures.

Amount: £2,331,140
Funder: The Wellcome Trust
Recipient: Newcastle University

ROS via RET: a redox regulated pathway to extend lifespan 17 Jul 2018

Reactive Oxygen Species (ROS) play a dual role in cellular physiology. On one hand, ROS are damaging oxidants that have been proposed to cause ageing. On the other, ROS are essential messengers required for maintaining cellular homeostasis. The aged and sick accumulate defective mitochondria that generate high levels of ROS, but antioxidant therapies fail to improve prognosis or extend lifespan. Furthermore, increasing mitochondrial ROS levels in animals extends lifespan rather than reducing it. A new paradigm explains these contradictory results proposing that under normal physiological conditions, ROS are only produced at specific sites (e.g. mitochondria) by specific ROS generators (e.g. respiratory complex I) which regulate distinct redox signalling pathways. Conversely under pathological conditions ROS are produced at unspecific places causing oxidative stress. My laboratory has characterized the first site-specific ROS signalling pathway which regulates animal lifespan: ROS produced via reverse electron transport (RET) at respiratory complex I. This proposal will fully characterize this new redox signalling pathway by addressing three aims: (i) identify the genes and proteins involved in the initiation, amplification and neutralization of ROS-RET, (ii) understand when and where ROS-RET needs to be activated to extend lifespan, and (iii) dissect the pathological consequences of dysregulation of ROS-RET signalling.

Amount: £1,512,586
Funder: The Wellcome Trust
Recipient: Newcastle University

Investigating the physiological DNA replication initiation reaction 30 Nov 2016

In all cells chromosome replication requires key initiator proteins to unwind the DNA at specific sites termed origins. Despite the fundamental importance of DNA replication initiation, crucial aspects of the process remain poorly understood. My vision is to identify all essential features of both the bacterial replication origin and DNA replication initiation proteins in vivo. This comprehensive reverse genetic analysis will guide biochemical investigations into the activities associated with deleterious mutations, thereby revealing the interactions and steps necessary for the physiological initiation reaction. Towards this goal I have created a bespoke tool: an inducible heterologous replication initiation system that allows construction and characterization of mutations within endogenous replication initiation factors. This methodology, combined with assays we developed to analyze DNA replication initiation in vitro, led us to identify a new essential bacterial replication origin element (Richardson et al. Nature 2016). We will build upon this successful approach and go on to develop more sophisticated heterologous replication systems, opening the door to studying all aspects of chromosome replication. Importantly, the bacterial DNA replication machinery is an underexploited drug target. Knowledge of bacterial DNA replication resulting from this work will provide a guide for disrupting this process in pathogenic species.

Amount: £1,535,316
Funder: The Wellcome Trust
Recipient: Newcastle University

A study of the interactions between proteins involved in chromosome segregation in Bacillus subtilis using the yeast-two-hybrid system 27 Apr 2017

During sporulation in the bacterium Bacillus subtilis, one of the sister chromosomes is translocated into the developing prespore. This mechanism is a useful model for studying chromosome segregation, a process which is vital in all organisms. The exact mechanism of chromosome segregation in sporulating B. subtilis is not fully understood. A protein complex, involving many proteins including Soj, Spo0J, MinD, MinJ, RacA, ComN and DivIVA, is known to anchor the origins of the sister chromosomes at opposite cell poles. We propose to test the direct interactions between members of this protein complex using yeast-two-hybrid assays. To begin with we will test interactions between the proteins Soj, Spo0J and MinD. Each of these are known to form dimers, and results from genetic and cell biology studies show that interactions between Soj-Spo0J and Soj-MinD are important for the anchoring of the chromosome origins to the cell poles. These latter interactions have not been shown directly and we aim to test these in this project. The project will hopefully move on to test further protein interactions in the complex, including those with RacA and ComN. Any interactions observed between these proteins will further our understanding of chromosome segregation in B. subtilis.

Amount: £0
Funder: The Wellcome Trust
Recipient: Newcastle University

Understanding the role of autophagy in the pathogenesis of AMD using a patient specific iPSC model 27 Apr 2017

AMD remains the most important cause of blindness in the elderly. The number of AMD affected people in UK is expected to rise to 1.3 M by 2050 with healthcare costs rising to £16.4 billion during 2010-2020. Currently there is no effective treatment hence a huge unmet need for investigations into therapies. This project aims to contribute to the identification of the underlying causes of AMD by interrogating a new cell model created by the host lab. Preliminary data suggest that autophagy, a process by which the cells remove waste products, is impaired in retinal pigmented epithelial cells derived from patients with AMD, leading to deposition of waste products and increased stress. Using this model, I will investigate which step of the autophagic process is not functioning properly in retinal cells, thus leading to a better understanding of AMD etiology. To date, small molecules that regulate autophagy are used in clinical trials of other neurodegenerative diseases. By the end of this project we will find out if the existing small molecules restore the autophagy in retinal cells of AMD patients. This will contribute to the design of preclinical studies for preventing further progression of AMD and restoring sight loss.

Amount: £0
Funder: The Wellcome Trust
Recipient: Newcastle University

How early visual cortex encodes the binocular statistics of the natural world 30 Sep 2017

Stereoscopic “3D” depth perception relies on sensing small disparities between the images viewed by the left and right eyes. Comparing the two eyes’ images and extracting these disparities is a complex process which begins in the brain’s primary visual cortex (V1). Many neurons in this cortical area are sensitive to binocular disparity, even when no other depth cues are present. I want to understand how they achieve this. Current neural network models capture many aspects of this computation, but real neurons seem better adapted to the statistics of the real world than current models can explain. I plan to record from individual neurons in the primary visual cortex as many thousands of stereoscopic images are viewed. I will exploit new analytical techniques to fit more sophisticated models. I will explore how current models fail, e.g. by failing to capture how real neurons respond to differences in contrast and spatial frequency. I will then modify current models, e.g. by incorporating divisive normalisation. I hope this will produce new insights into how the two eyes’ images are combined in the brain, with benefits to other aspects of perception.

Amount: £80,000
Funder: The Wellcome Trust
Recipient: Newcastle University

Open access block grant 2016/17 30 Sep 2016

Not available

Amount: £115,275
Funder: The Wellcome Trust
Recipient: Newcastle University

Does sleep play an important role in the consolidation of learned motor skills? 01 Apr 2016

"During sleep the brain cycles between slow-wave sleep (SWS) and rapid eye movement (REM) sleep. Little is known about the role of cortical activity during sleep. Evidence suggests that sleep is important for consolidation of memories and skills acquired during the day, but the mechanisms by which this occurs are not known. Most research into brain activity during sleep uses electroencephalography (EEG), which does not allow the activity of individual neurones to be examined. We have used implanted electrodes and wearable data loggers to record the action potentials discharged by multiple neurons and local field potentials in the motor cortex 24 hours a day during natural behaviour and sleep. This project will use this existing dataset to: Characterise the activity patterns of individual neurones in different sleep phases Assess the degree to which brain cells are synchronised with oscillatory activity observed in local field potentials at different frequencies Characterise patterns of correlation between different neurones at these frequencies "

Amount: £1,500
Funder: The Wellcome Trust
Recipient: Newcastle University
Amount: £156,073
Funder: The Wellcome Trust
Recipient: Newcastle University

Accurate and patient-friendly measurement of binocular visual function using a 3D smartphone 28 Nov 2013

Stereo vision, often called 3D vision, is the ability to use both eyes together to see depth. Clinicians use specialised vision tests, called stereotests, to measure patients’ 3D vision in disorders like squint. This helps them monitor progress, assess whether treatment is helping, and can guide decisions like when to operate.However, existing stereotests are not very reliable. Young children may not understand the test or be willing to cooperate, e.g. by wearing 3D glasses. This limits the usefulness of current stereotests. Recently, the first glasses-free 3D tablet computers have come on the market. A team led by Dr Jenny Read at Newcastle University wants to use these to produce a better stereotest. For children, the stereotest will be embedded in a fun, colourful game. Patients will give their answers by touching the screen. The device will use these responses to interactively adapt the test for that particular patient, customising it for each individual. The device will monitor patients while they do the test and automatically correct for any changes in viewing distance. As a result, it will provide clinicians with more accurate data on 3D vision, especially in small children. This will help healthcare professionals to track the progress of treatment and make the best clinical decisions.

Amount: £368,397
Funder: The Wellcome Trust
Recipient: Newcastle University
Amount: £1,202,412
Funder: The Wellcome Trust
Recipient: Newcastle University