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Regulation of microglial phagocytosis 30 Sep 2018

Microglia are the brain's immune cells. They constantly survey the brain to search for invading micro-organisms, unwanted molecules (such as amyloid plaques in Alzheimer's disease) or dying cells, but also play a key role in sculpting the circuitry of the brain by removing unnecessary cells and synapses during development. The mechanisms by which microglia constantly move their processes to survey the brain, and then remove invading micro-organisms, plaques, cells or synapses, are poorly understood. I will use 2-photon and confocal imaging techniques to investigate these events, taking advantage of recent discoveries from the Attwell lab which have revealed the importance of microglial potassium channels and purinergic receptors in controlling these events.

Amount: £0
Funder: The Wellcome Trust
Recipient: University College London

Characterising the neural mechanisms of human memory at high resolution 10 Apr 2018

Our past experiences are captured in autobiographical memories that serve to sustain our sense of self, enable independent living and prolong survival. Despite their clear importance and the devastation wreaked when this capacity is compromised, the neural implementation of autobiographical memories has eluded detailed scrutiny. My goal is to understand precisely how autobiographical memories are built, how they are re-constructed during recollection and how these memory representations change over time. My aim is to identify the mechanisms involved in these processes and thereby establish a theoretically enriched account of their breakdown in pathology. This endeavour will be enabled by cutting-edge, multi-modal technology that includes a new wearable MEG system and ultra-high-resolution MRI. The ventromedial prefrontal cortex and hippocampus are heavily implicated in autobiographical memory. I will test a novel hierarchical model that specifies their distinct roles and how they interact to produce the seamless encoding and recollection of our lived experiences. Overall, this new extension of my work will expose autobiographical memories as never before, revealing the millisecond temporal dynamics, and the laminar-specific and hippocampal subfield processing that supports their evolution from the point of inception, through initial sleep cycles and then over longer timescales.

Amount: £2,359,757
Funder: The Wellcome Trust
Recipient: University College London

Gene Editing using CRISPR/Cas9 for Gene Correction in Recessive Dystrophic Epidermolysis Bullosa (RDEB) 31 May 2018

Conventional gene therapy approaches rely on the addition of a corrected gene copy via viral vector transduction. Such strategies are currently being applied to recessive dystrophic epidermolysis bullosa (RDEB) where there is defective collagen type VII protein. However, use of constitutive exogenous promoters in viral vectors results in sustained gene expression that is not subject to the normal regulatory mechanisms of C7 expression. Integrating properties of vectors also pose risk for insertional mutagenic-derived events and efficiency of gene transfer has been challenging given the large size of COL7A1 cDNA. Whereas, gene-editing tools can be designed and engineered to target and repair specific defined regions of DNA, thereby alleviating genomic toxicity and maintaining endogenous gene expression control. Existence of well-known mutation hotspots within COL7A1 allows CRISPR reagents to be designed that would target the mutations found in the UK population with RDEB. Investigations outlined in this proposal aim to identify the most effective CRISPR reagent for a chosen mutation hotspot within COL7A1 gene. In skin, keratinocytes predominantly produce collagen type VII. Therefore, this project will evaluate feasibility of gene editing approaches using CRISPR/Cas9 system in HACAT keratinocytes cell line, and help address critical aspects of CRISPR/Cas9 efficiency at a chosen loci.

Amount: £0
Funder: The Wellcome Trust
Recipient: University College London

Serine ADP-ribosylation in genome stability and human disease 10 Apr 2018

ADP-ribosylation (ADPr) is a post-translational modification (PTM) of proteins, synthesised by the poly(ADP-ribose) polymerase (PARP) family of enzymes. Through the modification of a variety of mediator/effector proteins, PARPs control cellular processes that are critical for genome stability, including DNA repair, regulation of chromatin structure, transcription, apoptosis and mitosis. However, the proteins involved in these pathways and their mechanisms of regulation remain poorly understood. Recently, we identified ADPr on serine residues in proteins (Ser-ADPr) as a previously unknown PTM. We showed that Ser-ADPr synthesis is dependent on histone PARylation factor 1 (HPF1), a recently identified specificity factor and interactor of DNA repair PARPs - PARP1 and PARP2. We further showed that Ser-ADPr specifically targets proteins involved in the maintenance of genome stability. Finally, we also revealed that a hydrolase called ARH3 acts as specific enzyme for a timely reversal of Ser-ADPr. Our first goal of this project is to use biochemical and structural approaches to understand the exact molecular mechanism by which HPF1 and ARH3 work in the synthesis/removal of Ser-ADPr. Our second goal is to define the physiological processes controlled by Ser-ADPr and to understand how these processes are regulated in cells, using cell biology approaches and animal models.

Amount: £2,074,702
Funder: The Wellcome Trust
Recipient: University of Oxford

Politics, Philosophy and Economics of Health 30 Jun 2018

This project will examine benefits sharing for the provision of genetic information in the creation of medical treatments for infectious diseases. Networks to enable the international sharing of genetic material are a cornerstone of pandemic preparedness initiatives. Countries with the highest disease burdens share their isolated virus strains, that are utilised by pharmaceutical companies to create patented therapies, typically inaccessible to the citizens of the country from which they originated. The inequity of such a system is clear. In response to Indonesia’s 2006 protest, the Pandemic Influenza Preparedness Framework (PIP) was developed to facilitate benefits sharing. Uniquely, this framework set a standard of practice for governments, academics, and the private sector, and enabled it to be enforced through the use of civil contractual legislation. However, recent scientific and technological advancements, such as gene sequencing data (GSD), may serve to diminish the framework’s capacity to promote global health justice. Through an evaluation of the effectiveness and equity of current policy, this research attempts to highlight areas of tensions that arise in light of recent innovation. If left unaddressed, these new gaps could impede the goal of fairness that these policies set out to achieve, directly impacting the health of individuals globally.

Amount: £27,140
Funder: The Wellcome Trust
Recipient: University College London

Expanding the Inventory Records and Online Profile of Early Modern Medical Books at the Science Museum 18 Jun 2018

The short-term goal of my six-month project is to create a new inventory of the Science Museum’s 158 pre-1800 medical books which would contain more up-to-date, detailed information about the contents, physical format and publication circumstances of the predominantly Latin and English codices. I also intend to explore and document links between the books and the museum’s large collection of medical objects. My project will also contribute to the long-term goal of making the books more accessible by the museum’s online search platforms. Consequently, part of my project may involve developing contextual materials to accompany the books, such as more in-depth, accessible information about the authors, the broader concepts they are engaging with, and their place within the history of medicine. I would also be keen, if possible, to increase the online presence of these books by writing a short, informal and engaging article aimed at the general public for the Science Museum Blog, or a more formal article on the process of cataloguing them for the Science Museum Group Journal.

Amount: £13,005
Funder: The Wellcome Trust
Recipient: University of Oxford

Global Health 50/50: Towards accountability for gender equality in global health 04 Dec 2017

We propose to establish Global Health 50/50, a new initiative seeking to advance action and accountability for gender-equality in global health. Gender is a key driver of power to exercise the right to health, including exposure to risks of poor health, health seeking behaviours, and access to quality health care. Gender inequalities continue to define and drive career pathways and opportunities for people working in global health organizations. While some progress has been made, major gaps and challenges remain. We seek to raise awareness of persistent inequality and identify pathways to change. We will establish a network of experts in gender and global health, working with an advisory body drawn from the realms of politics, development, management, advocacy, human rights, social justice. Global Health 50/50 will publish an annual report on the state of gender-related policies and practices of 150 major organizations working in the field of global health.

Amount: £29,764
Funder: The Wellcome Trust
Recipient: University College London

Public health data science to investigate and improve migrant health. 25 May 2017

Migration is a defining political challenge of our time and a global health priority. Internationally there is a lack of epidemiological data on new migrants including the prevalence of high morbidity conditions and estimates of risk factors for disease. The overarching aim of this research is to generate evidence that will improve the health of migrants moving from low and middle-income to high-income countries. Key goals: Million migrant study: Create an electronic cohort that will establish the first national rates of age-specific morbidity and risk factors for disease in migrants. Migrant eCohort: Investigate the migrant exposome and how this changes over time since migration, using digital technologies (smart phones and apps) for data collection. Personalised public health intervention: Develop and test the feasibility of a tailored health advice website to improve migrant health. Outcomes: These studies will transform how we conduct digital cohorts in mobile populations and have wide application for efficient study design. The detailed epidemiological and health service data produced will provide the first national evidence of the health effects of rapid epidemiological transition as a result of UK migration, and a platform from which to carry out digitally enabled personalised public health interventions.

Amount: £1,164,786
Funder: The Wellcome Trust
Recipient: University College London

Using visual dysfunction to understand dementia in Parkinson’s disease 06 Dec 2016

Dementia affects half of patients with Parkinson’s disease (PD) but there are no robust measures to predict who is at highest risk. Visual hallucinations are highly distressing to patients and carers but are poorly understood. This Fellowship will use visuo-perceptual dysfunction to predict dementia and understand hallucinations in PD. I have developed a novel test using skewed images to detect visuo-perceptual deficits in Parkinson’s patients. I have also developed a web-based platform to enable this and other visual tests to be accessed by large numbers of patients with PD. In this proposal I will use visual perceptual tests combined with neuroimaging over time to determine the sequence of visuo-perceptual deficits in PD. I will relate these to changes in hallucinations. I will use my web-based platform to identify clinical and genetic associations with visual deficits and determine their role in predicting dementia in PD. Goals 1. Characterise changes in visuo-perception as PD progresses and correlate deficits with brain atrophy. 2. Relate MRI structural connectivity changes with disease progression. 3. Examine clinical and genetic associations of visual dysfunction in PD. 4. Test whether transcranial stimulation can improve visuo-perceptual function in PD. 5. Determine how visual hallucinations become distressing as PD advances.

Amount: £1,223,282
Funder: The Wellcome Trust
Recipient: University College London

Analysis of cytomegalovirus pathogenesis in a human challenge system 30 Nov 2016

Our research has made major contributions to understanding the natural history and pathogenesis of human cytomegalovirus (HCMV) in allograft recipients. Critically, we have demonstrated that biomarkers can be applied to stratify patients most at risk of HCMV disease and thus inform clinical practice to reduce HCMV end-organ disease. This clinical approach of administration of antivirals to individuals with elevated viraemia above designated levels provides a unique opportunity to gain fundamental insight into disease processes in a human challenge model of HCMV infection. A multi-disciplinary consortium has been recruited to apply next generation DNA sequencing, molecular virology and functional immunological assays to identify virus and host cell determinants of disease susceptibility. Whole genome sequencing of virus in organ donors (live and cadaveric) and recipients will be used to track the source, replication kinetics and evolution of HCMV strains in seronegative and seropositive recipients. We will then define in vitro humoral, cell-mediated immunity and natural killer responses against HCMV that correlate with protective immunity against primary infection, reinfection and reactivation in these patient groups. This approach has the potential to provide unique insights into the natural history and pathogenesis of HCMV and identify innovative therapeutic approaches against it.

Amount: £2,669,767
Funder: The Wellcome Trust
Recipient: University College London

Modelling the impact of poor quality antimicrobials on patient outcome and drug resistance – a pilot study to inform policy in the absence of empirical data 30 Sep 2017

Antimicrobial resistance (AMR) is an increasingly serious and pressing global public health problem. Poor antimicrobial quality is increasingly realised as an important rectifiable impediment to global public health. There has been little discussion or evidence as to its comparative importance, in relation to other drivers such as poor prescribing and adherence, for both poor patient outcomes and AMR. In the absence of field data on the relationship between AMR and antimicrobial quality, mathematical modelling based on pharmacokinetic-pharmacodynamic relationships and rates of genetic change provides estimates which can be used to predict outcomes and inform policy. We propose a two phase modelling approach examining how poor quality essential medicines may affect patient outcomes and resistance selection and spread, modelling in Phase 1 antimalarials and in Phase 2 anti-tuberculosis and anti-hepatitis C medicines. This pilot project will build on the existing Wellcome investment in the Mahidol Oxford Research Unit (MORU) Network (though core funding) and the Infectious Diseases Data Observatory (through the MAPQAMP Biomedical Resources grant and core funding) for modelling, PK/PD and medicine quality resources and skills. The growing interest in medicine quality by nations and international organisations and the invitation by the WHO Member State Mechanism (on medicine quality) to the IDDO/MORU Medicine Quality Group to be a stakeholder, facilitates synergistic discussions with multiple partners and nations. We are also discussing expanding our collaboration with the United States Pharmacopeia PQM program on medicine quality & AMR. We are organising the first Conference on Medicine Quality & Public Health for September 2018 and we intend that the initial results from this work would be presented at this meeting. This project will therefore give the first objective evidence, rather than opinion, on the importance, or otherwise, of medicine quality on patient outcome and AMR, in comparison to poor adherence and poor prescribing. It will link in extremely well with the diverse activities of the MORU Network, IDDO, WHO, USP and diverse other stakeholders and be opportune for influencing policy for both medicine quality and AMR. This project will be linked to the parallel project proposed to Wellcome by Dr Elizabeth Pisani on ‘Understanding the political barriers to tackling sub-standard and falsified medicines’.

Amount: £99,994
Funder: The Wellcome Trust
Recipient: University of Oxford

Effective public policy for improving sexual health of migrants/refugees 30 Sep 2017

Summary: Identifying and implementing appropriate and effective public policy responses for improving the sexual health of migrants and refugees Global challenges are complex, interwoven "wicked problems" whose solutions require systemic thinking, cross-disciplinary collaboration, and engagement with a range of stakeholder opinions and positions. In this proposal we will address the interlinked problems of inequalities, migration/refugees and global health. Using the tracer example of sexual health (sexually transmitted infections including HIV) we will explore rigorous evidence for interventions to address upstream determinants driving poor health outcomes for refugees/migrants from West Asia/Middle East North Africa (WA/MENA). Results from systematic reviews, realist reviews and mathematical modelling will be synthesised to identify effective interventions which can be translated into policy (in a range of sectors). These policy options will be assessed and refined to enhance their ‘palatability’ – i.e. their legitimacy, feasibility and acceptability with a range of key stakeholders in countries in the WA/MENA region as well as in pan-EU and national level (UK) health institutions.

Amount: £673,516
Funder: The Wellcome Trust
Recipient: University College London

Understanding the functional role of GABA across the human motor network 05 Dec 2016

Understanding the functional role of GABA across the human motor network

Amount: £214,011
Funder: The Wellcome Trust
Recipient: University of Oxford

Advancing Psychiatric Mapping Translated into Innovations for Care: PsyMaptic-A 05 Dec 2016

My current and previous Wellcome Trust Fellowships (Henry Wellcome, 2009-13; Henry Dale 2014- present) focus on important aetiological questions about psychotic disorders, using epidemiological data. Psychotic disorders are a debilitating set of mental health disorders, characterised by hallucinations, delusions and cognitive deficits. My research demonstrates that these disorders have a robust, replicable social aetiology, with higher incidence rates observed in young people,1–3 men,1–3 ethnic minorities2–7 and people exposed to greater social disadvantage.8–11 In my previous fellowship, I established the largest epidemiological study of first episode psychosis [FEP] in England since 1999, to demonstrate that these substantial mental health inequalities also exist in more rural populations (East Anglia)3,12; rates are over twice as high as expected,3,13 with deprived rural communities experiencing the highest psychosis incidence. This study has generated new Page 5 of 18 aetiological clues, for example by showing that people at "ultra-high risk" of psychosis are exposed to similar social and spatial markers of social disadvantage as FEP patients,14 implicating an aetiological role for social adversities prior to onset. I have also demonstrated that migrants face greatest FEP risk when immigrating in childhood,15 an important period of sociocognitive development. I am attempting to replicate this in my current Fellowship, in a larger longitudinal cohort using Swedish national register data. Using this data, I have already shown that refugees are at elevated psychosis risk compared with other migrants from the same region of origin,7 providing further insights into the possible social determinants of psychosis. Epidemiological data can also inform mental health service planning. In England, Early Intervention in Psychosis [EIP] services assess and treat people with suspected FEP, offering evidence-based multidisciplinary care to improve downstream clinical and social outcomes, shown to be highly costeffective.16 Unfortunately, original policy implementation guidance17 made no provision for the heterogeneity in incidence described above, with services commissioned on a uniform expectation of 15 new cases per 100,000 people-per-year. This was at least half the true incidence,1,3 and over three times lower than the overall referral rate for all suspected FEP, including "false positive" (nonFEP) referrals,3 who still require appropriate psychiatric triage and signposting, and consume additional EIP resources not factored into original guidance. In response, I demonstrated that epidemiological estimates of psychosis risk could be used to better predict the expected FEP incidence in the population at-risk in England,13 nationally and regionally. The tool, known as PsyMaptic, has had substantial impact on policy and commissioning since it was freely-released in 2012 (www.psymaptic.org).16,18–22 Most recently, it has been used to inform national EIP workforce calculations23 following the introduction of Access and Waiting time standards,19 as part of the Department of Health’s commitment to achieving parity of esteem between mental and physical health by 2020.24 Whilst I have demonstrated, via PsyMaptic, that it is possible to translate epidemiological data into effective public mental health,25 some vital methodological limitations require empirical attention. I therefore seek Wellcome Trust enhancement funding to answer four empirical questions to develop and apply novel statistical prediction methodologies to generate sustainable, dynamic populationbased models of future mental health need.

Amount: £204,479
Funder: The Wellcome Trust
Recipient: University College London

Novel statistical methodology for rare variant association in a case-control cohort 30 Sep 2018

Genetic association studies focusing on common variation have uncovered only a fraction of proposed trait heritability. Some of this so-called missing heritability will be found within rare variation in the population. This hypothesis is supported by the facts that recent explosive population growth has increased the population burden of rare variants and deleterious variants are kept at low allele frequencies. All genetic susceptibility to disease is caused by alterations to the genes or their expression and for this reason it seems fruitful to focus an association study on the genes themselves. Any associations found are then directly informative about the molecular basis of disease without the need for fine mapping. The proposed project aims to develop a statistical method to find genes associated with disease by analysing the rare variation present in a case-control cohort. We aim to extend existing methods by including a previously unconsidered parameter; the position of the variants in a gene. In scenarios where differences in clustering or distribution of variants are observed between cases and controls, this method will have a substantial increase in power. This technique will be useful for elucidating the molecular mechanisms causing the disease and thus discovering new therapeutic targets.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Oxford

Design and evaluation of a modified vaccinia Ankara vector therapeutic vaccine for hepatitis B immunotherapy 30 Sep 2018

Hepatitis B virus (HBV) is a serious global health problem, with approximately 240 million people chronically infected. Long-term infection can lead liver failure, cancer and death. Current therapy controls but does not eradicate the infection. T cells are a type of immune cell necessary to fight HBV. During chronic hepatitis B these cells become less active. Checkpoint inhibitors are a form of immunotherapy that enables T cells to function again. In a study of woodchucks infected with a similar virus to HBV, treatment with vaccine and checkpoint inhibitor lead to better control of the virus. This project aims to use this combination of vaccine and checkpoint inhibitor, to treat patients with chronic HBV. A vaccine using a virus to carry the HBV proteins has been developed and shown to generate good immune responses in mice. We plan to develop a second vaccine to boost this response and test the vaccines together with checkpoint inhibitors in mice infected with the HBV virus. This will allow us to assess how effective this is at eradicating HBV. If the results from this study are promising, this could pave the way for clinical trials in humans with chronic HBV.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Oxford

Probing nucleotide interactions with Kir6.2 using fluorescence spectroscopy. 30 Sep 2018

The ATP-sensitive potassium (KATP) channel is a plasma membrane protein present in beta cells of the pacreas which plays a key role in insulin secretion. KATP acts as a metabolic sensor, alerting the beta cells when blood glucose raises too high and stimulating them to release insulin. In diabetes, normal KATP function is disrupted and beta cells no longer secrete insulin properly in response to blood glucose levels. The molecular structure of the channel is closely linked to its function; there have been several genetic studies linking various mutations (which often only affect one molecule in the channel!) to neonatal diabetes or increased propensity to type II diabetes. Our research aims to identify precisely how these small mutations can have such drastic changes in the activity of the channel by using a combination of fluorescent labels and channel current measurements to watch the KATP channel move in real time. We can then try to construct a model of how the channel converts different stimuli into movements, and how this is affected in mutations linked to diabetes.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Oxford

Regulated mRNA stability and translation in neural stem cell development 28 Nov 2017

Understanding how the billions of varied cells in the human brain develop from a small number of neural stem cells (NSCs) is a central question in biology and medicine. This highly complex process has largely been explained by transcriptional regulation dictating the levels of protein expression in stem cells and their progeny. Using novel single molecule approaches to quantitate transcription and protein levels, we have discovered functionally important conserved examples where the levels of transcription and protein expression do not correlate. These include pros/prox1, the regulator of NSC proliferation and differentiation and myc, the proto-oncogene regulator of stem cell size. We will characterise the mechanism of post-transcriptional regulation of pros, myc and 21 additional functionally important examples we have discovered, all of which have extremely long 3’UTRs that are bound and regulated by the same conserved RNA binding proteins, Syp and Imp. We will also measure, genome-wide, mRNA stability and characterise the trans-acting factors and cis-acting signals regulating stability and translation. The proposed programme will characterise a hitherto under-studied layer of regulation acting in addition to transcription in complex tissues, providing major new mechanistic insights into how the brain develops in health and disease.

Amount: £1,972,007
Funder: The Wellcome Trust
Recipient: University of Oxford

Co-evolution of tumour mutational and CD4 T-cell differentiation landscapes 30 Sep 2018

Lung cancer is the second most commonly diagnosed cancer in the UK and the greatest cause of cancer-related death. A type of this disease called non-small cell lung cancer (NSCLC) accounts for the majority (85%) of cases. T-lymphocyte cells (T-cells) of the immune system patrol the body and can recognise and destroy cancer cells by recognising mutated proteins (neoantigens) on them. Despite this, the majority of patients with advanced lung cancer die of the disease, indicating the ineffective function of the immune system. In particular, little is known about the role of a particular group of immune cells called T-helper cells that are thought to be important. In chronic infections where T-cells are constantly exposed to their targets, they become less responsive as younger cells are driven to turn into later ones more rapidly. As younger cells are lost, the body's ability to fight the infection reduces. In cancer, it is possible that mutations drive a similar problem. Using lung cancer specimens from patients on a clinical trial and animal models of cancer, we propose to study the question of whether and how mutations can paralyse the ability of T-helper cells to fight the disease.

Amount: £0
Funder: The Wellcome Trust
Recipient: University College London