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Results

Measuring frailty in older rural South African population - Construction and validation of a Frailty Index 31 May 2018

Data from the HAALSI cohort from rural South Africa will be used to achieve 3 aims: To derive a Rockwood deficit-accumulation Frailty Index (FI) in this population To test whether the FI predicts mortality in the HAALSI population To compare results from the Fried frailty score and the FI A review of existing literature will inform the selection of a minimum of 30 variables for inclusion in the Frailty Index. Examples include (but are not limited to): disease diagnoses (e.g. angina, HIV), functional impairments (e.g. low gait speed, low grip strength), or biochemical/haematological derangements (e.g. low haemoglobin). Absence of a deficit scores zero; presence of a deficit scores 1. Cox proportional hazards models will be used to examine the association between the FI and time to death in the HAALSI data; unadjusted models and models adjusted for age and sex will be developed. Finally, the ability of the FI to predict 1 year mortality will be compared with the ability of the Fried phenotypic score to predict 1 year mortality in the HAALSI population. Receiver-operator characteristic curves will be developed for each score, and the c-statistic for each score compared.

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

Newcastle Wellcome Trust Translational Partnership 30 Sep 2018

The partnership will help to engage our talented scientists in translational research by providing mentorship, support and addressing barriers in the early stages of the translational pathway, while creating an embedded and durable cultural awareness of translation in all of our scientists.

Amount: £800,000
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

Modulation of the upper airway host defences to prevent pneumonia in ventilated patients. 24 Jun 2015

Ventilator-acquired pneumonia (VAP) is the commonest fatal hospital-acquired infection. It arises from colonisation of subglottic epithelium with pathogens that are micro-aspirated into the lung. Preventive strategies for VAP are significantly hampered by lack of a cellular model. My preliminary work generated human primary subglottic epithelial air-liquid interface cultures (SEALICs) for the first time. Hypotheses: -Increased mucin production by the subglottic epithelium of critically ill mechanically ventilated patients promotes growth of VAP pathogens and impairs neutrophil function. -Down-regulation of mucin expression reduces growth of VAP pathogens. -Phagocytosis of VAP pathogens can be promoted in subglottic epithelium by over-expression of phagocytic receptors. Experimental Phases: -Derive SEALICs from critically ill intensive care unit (ICU) patients; compare mucus composition and pathogen binding, in ICU patients and controls. -Isolate human neutrophils and apply these to purified human mucin. -Use a myristoylated alanine-rich C-kinase substrate (MARCKS) related peptide to reduce mucin expression in my SEALIC model -Transfect SEALICs with phagocytic receptor genes and assess whether this augments their capacity to ingest and kill bacteria. The research is therefore expected to -consolidate a unique model of VAP pathogenesis -suggest novel ways to prevent VAP -provide me with broad training as a clinician-scientist.

Amount: £220,109
Funder: The Wellcome Trust
Recipient: Newcastle University

Bases for auditory cognition. 01 Apr 2015

Auditory cognition is the mechanism for making sense of the acoustic world. This is a necessary basis for the understanding of speech, environmental sounds and music that interacts with common hearing loss and is affected by common brain disorders. The work extends my approach to auditory cognition using synthetic stimuli that are statistically similar to natural stimuli. The work addresses two critical and broad systems for auditory cognition: auditory figure-ground analysis and working memory. The two human systems would be defined by modelling neurophysiological data acquired non-invasively (magnetoencephalography) and invasively (neurophysiology on neurosurgical subjects). Pilot work suggests systems for auditory figure-ground analysis involving auditory and parietal cortex and for working memory involving auditory cortex, frontal cortex and hippocampus. In particular, the work tests whether these systems obey the principle of predictive coding with prominent backward connectivity from high-level areas to auditory cortex. My previous work on perception supports this idea, but application of predictive coding to auditory cognition in general is controversial. Human clinical work would establish how these two systems contribute to speech-in-noise detection deficits in cochlear hearing loss and how common brain disorders affect the two systems.

Amount: £1,718,617
Funder: The Wellcome Trust
Recipient: Newcastle University

Cyclin B1, critical regulator of the timing of cell division. 14 Apr 2014

A critical aspect of the cell cycle is the maintenance of high levels of cyclin B1 at metaphase followed by its rapid APC driven destruction as chromosomes segregate. Impaired regulation of cyclin B1 at this stage of the cell cycle is firmly associated with aneuploidy. Knowledge of cyclin B1 control is largely limited to studies in mitotic cells. Here I will address for the first time whether mechanisms differ between mitosis and meiosis. Indeed preliminary data provide strong evidence to sugges t vastly differing regulation and have therefore led to the design of experiments to fully characterise this. Specifically; to determine how cyclin B1 is recognised by the meiotic destruction machinery and to detail the mechanistic implications of differential spatial control of both cyclin B1 and the APC in meiosis and mitosis. Differential cyclin B1 control mechanisms ultimately point towards the existence of meiosis specific APC activator. A key goal of this project will be to uncover its identity and detail a role in both vertebrate and invertebrate meiosis. A full understanding of the physiological process which regulate cyclin B1 and metaphase exit is important since errors are not uncommon and have a great negative impact on human health.

Amount: £104,041
Funder: The Wellcome Trust
Recipient: Newcastle University
Amount: £1,202,412
Funder: The Wellcome Trust
Recipient: Newcastle University

Clinical Study of the Effectiveness and Safety of Pronuclear Transplantation 30 Sep 2016

Prof. Mary Herbert, Prof. Sir Doug Turnbull and colleagues published the first preclinical studies of pronuclear transplantation (PNT) on normally fertilised human zygotes in June 20161. In depth analysis revealed that "early PNT" does not adversely affect human development and greatly reduces the level of dysfunctional mitochondria in the embryo. This publication represents completion of the final scientific studies requested by the Human Fertlisation and Embryology Authority expert scientific review panel, paving the way for a clinical application to be submitted (likely in early autumn).2 Prof Turnbull now proposes to carry out a clinical study to evaluate the effectiveness and safety of mitochondrial donation in humans. The study will involve monitoring the fetal and postnatal development of 25 children conceived using the technique and to perform expert assessment of development in 5 areas (cognitive, motor, language, socio-emotional; and adaptive behaviour) at 18 months. The requested funding will cover clinical staff time, equipment, travel costs related to patient assessment and sample collection/analysis. Joint / collaborative funding At this stage exploration of mitochondrial donation includes both lab-based research and clinical research elements. It is therefore appropriate that the funding model reflects these different aspects. Following discussions, NHS England has agreed to meet treatment and clinical care costs as part of this research proposal, which represents the majority of the resource, with Wellcome funding the other components.

Amount: £201,869
Funder: The Wellcome Trust
Recipient: Newcastle University

Institutional Strategic Support Fund 07 Sep 2016

Not available

Amount: £2,250,000
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

Use of primary airway epithelial cells from children with cystic fibrosis to investigate novel anoctamin 1 activators 29 Jun 2016

Cystic fibrosis (CF) is the most common genetic life-limiting disease in the UK. Lifelong treatment burden is significant but despite this death occurs early in life due to respiratory failure. Dysfunctional CF transmembrane conductance regulator (CFTR) protein leads to defective apical airway chloride and bicarbonate transport, resulting in a dehydrated and acidic airway surface liquid (ASL), impaired mucociliary transport and progressive lung disease. Latest strategies directed at correcting dysfunctional CFTR will not benefit all people with CF and alternative approaches are required. Activation of an alternative apical chloride/bicarbonate channel, anoctamin 1 (ANO1), could bypass the effects of dysfunctional CFTR and mitigate subsequent ASL volume and pH abnormalities. To investigate this, I will characterise the electrophysiological profiles of paediatric human primary nasal (PBEC) and bronchial airway epithelial (PBEC) cells to further validate PNEC use as a paediatric CF drug discovery tool. Using these models, I will investigate ANO1 expression and the effects of novel small molecule ANO1 activators on electrophysiological profile, ASL height and pH. This fellowship will provide novel information regarding ANO1 activation using this airway epithelial model and help determine the role of these compounds as a potential CF therapeutic strategy. Keywords: Cystic fibrosis, Epithelium, Children, Airway, Anoctamin 1

Amount: £157,652
Funder: The Wellcome Trust
Recipient: Newcastle University

The Everyday Cyborg: Mapping Legal, Ethical, & Conceptual Challenges 10 Mar 2016

Everyday cyborgs are all around us. They are persons with replacements and augmentations ranging from the simple to the extraordinarily complex; for example, artificial joint replacements, implanted devices such as pacemakers and the total artificial heart, and limb prostheses. These parts and devices may be completely artificial, biological, or biohybrid in nature (a mixture of biological and synthetic components). Additionally, they may contain mechanical or electronic components and be capable of running software and storing data. This linking of the organic, biological person with synthetic, inorganic parts and devices raises questions which the law is ill-equipped to deal with. For instance, should internal medical devices which keep the person alive be viewed as part of the person or mere objects (or something else), is damage to neuro-prostheses (nervous system integrated) personal injury or damage to property, and is deactivation of the total artificial heart withdrawal of treatment or active euthanasia? Satisfactorily answering such questions requires a re-analysis of the conceptual and ethical terrain underpinning the law, as well as the law itself. This project will lay the groundwork for this by identifying, mapping, and beginning to explore the novel legal, ethical, and conceptual challenges posed by implantable and prosthetic technologies.

Amount: £49,409
Funder: The Wellcome Trust
Recipient: Newcastle University

State-of-the-art proteomics for Newcastle University 05 Jul 2018

Proteomics is a powerful tool that is increasingly used by scientists in a wide range of biologically and medically important areas. Here, we are requesting funds for a cutting-edge liquid-chromatography mass spectrometry (LC-MS) system that will enable us to support Wellcome-funded researchers in Newcastle with access to state-of-the-art proteomics. We will utilise this instrument to enhance the research of a number of exceptionally successful clinically relevant research groups. In particular, we will perform quantitative proteomics to identify changes to the mitochondrial proteome in response to disease mutations, characterise immune populations during early human development, the role of mutations in inflammatory disease in humans, analyse molecular pathways and identify biomarkers in liver disease and fibrosis, and describe molecular mechanisms in bacterial cell biology and pathogenicity. Overall, this instrumentation will boost the research of Wellcome-funded researchers at Newcastle University.

Amount: £578,689
Funder: The Wellcome Trust
Recipient: Newcastle University

An Extended Pilot for the Human Cell Atlas: Adult tissues, human development and inflammation-mediated pathologies 30 Sep 2018

The Human Cell Atlas (HCA) is an international, collaborative effort that "...aims to define all human cell types in terms of their distinctive patterns of gene expression, physiological states, developmental trajectories, and location". Here, we will contribute directly to the first phase of the HCA by forming an ‘extended pilot’ to implement UK infrastructure for large-scale, high quality human cell atlas experiments. We will generate a high-level atlas, with spatial resolution, for multiple adult human tissues along with matched data from human fetal material. We will then illustrate the power of a deep and focused investigation of a single tissue (skin) to produce highly-detailed data describing its cellular composition and spatial organisation. Finally, for selected tissues that have been profiled in adults and fetal material, we will analyse samples from immune-mediated disorders as a comparison with our reference data to gain deeper understanding of the pathological mechanisms. This will demonstrate the utility of the HCA as a ‘healthy reference’ for comparison with disease. Throughout, we will generate profound biological insight from primary human cells and lay a foundation of technology development and optimisation with a set of hardened and scalable methods for single-cell RNA-sequencing, spatially-resolved gene expression, and tissue imaging.

Amount: £849,370
Funder: The Wellcome Trust
Recipient: Newcastle University

MA in History of Medicine 11 Jul 2018

The Master of Arts in History of Medicine at Newcastle combines three modules common to all MA History programmes with three bespoke modules that deepen students’ understandings of medical history and develop their methodological and historiographical skills, in preparation for their dissertation. ‘Introduction to the History of Medicine’ provides an overview from antiquity to the twenty-first century, analysing the relationship between medicine and other aspects of Western and non-Western human civilizations; ‘The Patient in History’ examines how patients have been perceived, constructed and contested, and considers the extent to which the patient’s voice can be retrieved from different source materials; ‘Diseases in History’ analyses how diseases have been socially, culturally and historically understood, constructed and responded to. The core history modules are ‘The Practice of History’, which studies how historians have practiced their discipline in the second half of the twentieth century; ‘Research Skills and Dissertation Training’, which equips students with the practical skills required for dissertation work; and the 60 credit Dissertation module. Students select the independent study module, or a further MA module from within the Faculty of Humanities and Social Sciences. Assessment methods include research essays, a literature review, a poster, a dissertation proposal and the dissertation.

Amount: £78,132
Funder: The Wellcome Trust
Recipient: Newcastle University

Thinking forward through the past: Linking science, social science and the humanities to inform the sustainable reduction of endemic disease in British livestock farming 30 Jan 2018

Livestock disease today is a complex and pressing problem that threatens the development of more sustainable, ethical and efficient farming methods. This project will devise a fundamentally new approach to its investigation that advances understandings and informs responses. Cutting across the traditionally separate realms of nature and culture, science and society, human and animal, and past, present and future, experts in veterinary history, environmental economics, epidemiological modelling, human and animal geography, rural sociology and cultural history will work collaboratively across six institutions, and in close conjunction with stakeholders to investigate two major endemic health problems: Bovine Viral Diarrhoea in cattle, and lameness in cattle and sheep. Experiences of these problems in Britain since 1947 will be examined within four contrasting farming systems - upland and lowland ‘beef and sheep’, and indoor and pasture-based ‘dairy’ – to reveal how perceptions of, and responses to disease co-evolved with farming systems and communities, human-animal relationships, expert knowledge-practices, consumer attitudes, and wider political, economic and cultural contexts. Findings will inform - and be informed by - the development of epi-economic models that better predict the future incidence of, and farmer responses to disease, generating suggestions for how to mitigate its effects.

Amount: £376,696
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

The troubled immune system - molecular origins of immune dysregulation 11 Jul 2017

Immune-mediated inflammatory disease is a major and increasing cause of ill health worldwide. Effective therapy is hindered by our incomplete understanding of immune regulatory mechanisms and how to manipulate them. In this research project, we will focus on the molecular dissection of early onset immune dysregulation as a means to identify relevant genes and pathways in an unbiased way. We will use next generation sequencing to uncover causative mutations in children manifesting autoimmunity, autoinflammation and lymphoproliferation, sometimes in a familial way. We will characterize the diseased immune system in fine detail, using state-of-the-art technologies to learn as much as possible from small volumes of patient blood and tissue. We will study the role of the encoded proteins in vitro, modeling the effect of mutations and exploring the associated immunobiology. Finally we will create and study knock-in mouse models in which hypomorphic patient mutations are precisely engineered into the homologous murine gene. By these means we will gain maximal mechanistic insight from these experiments of nature, improve diagnostic and therapeutic outcomes for our patients and empower the development of new and better approaches to therapy of other immune-mediated inflammatory diseases.

Amount: £5,000
Funder: The Wellcome Trust
Recipient: Newcastle University

Decision Making in Pregnancy after 1970 10 Nov 2016

This pilot study will construct an application for the first large-scale historical analysis of the socio-cultural context of prenatal screening and diagnostic technologies, and their impact upon women and their partners. Parents’ decision making in pregnancy in Britain has been transformed over the past forty-five years by the development of prenatal screening methods, and invasive and non-invasive diagnostic technologies. These screening and diagnostic tests, which provide information about fetal genetic abnormalities, neural tube defects, other structural anomalies, and fetal gender, have been analyzed by sociologists, anthropologists and bioethicists. This pilot study will accomplish its goals by a) undertaking a rigorous literature review and scoping potential sources; b) holding workshops with academics, and stakeholders from medicine and the voluntary sector to inform the project’s design and approach, and to identify further sources, as well as collaboration and engagement opportunities; and c) to design a methodology for the project which enables women’s voices to be heard, and secure ethical approval for this methodology.

Amount: £29,894
Funder: The Wellcome Trust
Recipient: Newcastle University

A brain computer interface (BCI) to decode intended upper-limb movement online and in real-time 15 Sep 2014

Stroke is the main cause of acquired adult disability in high-income countries (Pollock et al., 2014). Annually, in England, approximately 110,000 people have a stroke (NHS Choices). Three quarters of patients suffering an acute stroke report upper-limb weakness (Lawrence et al., 2001) and 45% have limited fine-hand use 18 months after stroke (Welmer et al., 2008). No high quality evidence can be found for any current rehabilitative interventions to improve upperlimb function after stroke (Pollock et al., 2014). The ambition of this project is to combine recent advances in neuroimaging, data analysis and understanding of neuroplasticity to develop a new intervention for improving upper-limb function after stroke. This novel intervention will be developed with healthy participants assisted by contributions froma stroke patient focus group. Aims: 1. Investigate the patterns of neuronal activity associated with unilateral, symmetric bilateral and asymmetric bilateral upper-limb movements in healthy individuals. 2. Develop a brain computer interface (BCI) that decodes a user’s intention to perform an upper-limb movement. 3. Use the BCI to control a hand-orthosis that would allow users with limited hand movement to complete basic functional tasks. 4. Complete a feasibility study that demonstrates the orthosis and BCI to be acceptable and useable by upper-limb motor impaired stroke patients

Amount: £151,353
Funder: The Wellcome Trust
Recipient: Newcastle University