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The Wellcome Trust

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An Empirical Study of Children and Adolescents' Perspectives on Testing Minors for their Genetic Predisposition to Psychiatric Disorders 10 May 2016

Predictive genetic testing for psychiatric disorders could help prevent or delay the development of debilitating conditions. However, the complex inheritance, incomplete penetrance, and variable expression in the genes underlying mental disorders make such testing a relatively poor predictive instrument. Empirical studies investigated the socio-ethical impacts of such testing from the perspectives of adult patients, family members, psychiatrists, and geneticists, who highlighted the risk of promoting a deterministic stance on psychiatric conditions, of discrimination against and stigma of the individuals tested, and the potential negative effects on family relationships. However, no systematic study has investigated minors’ perspectives. This is an important gap in the debate, as minors are likely to be the main target of psychiatric genetic testing. Therefore, the aim of my research is to investigate children and adolescents’ perspectives on testing minors for their genetic predisposition to psychiatric disorders. My research will assess whether their concerns confirm those expressed in the academic literature and it will provide a more inclusive account of the public’s opinions, thereby promoting an ethically robust application of scientific discoveries in this field. I will conduct a systematic review of the ethics literature on psychiatric genetic testing in minors and a systematic qualitative interview study.

Amount: £93,065
Funder: The Wellcome Trust
Recipient: University of Oxford

‘Astrology is higher and nobler than medicine and every physician must be an astrologer’: Astrologer-Physicians and their Working Practices c. 1580-1680. 10 May 2016

My thesis will explore the working practices of early modern astrologer-physicians, as they were shaped and informed by the Astrological Figure. Broadly, the aims are twofold: firstly, to reconstruct the organisation, routines, rituals, encounters and processes of an early modern astrological-medical practice; secondly, to interrogate an astrologer-physician’s understanding and application of the evidence contained within the Figure. A number of new perspectives and important new research questions will be introduced: How did the Figure shape the processes of astrological-medical practice? How did the Figure inform an astrologer-physician’s construction and imaging of disease, illness or other condition in the body or mind? How did the Figure inform an astrologer-physician’s diagnosis, prognosis and treatment? How closely was astrological theory adhered to in terms of interpretation/response? Engaging with a fine level of detail, a unique combination of material will be analysed and integrated: printed vernacular astrological guides/manuscripts and astrological-medical casebooks. Personal correspondence, autobiographies and almanacs will be examined, together with astrologer-physicians’ source material. The structure of this thesis will follow the procedural steps of the early modern astrological-medical consultation (the Encounter, Process, and Response), simultaneously working within the classifications of astrology as presented in texts of the time.

Amount: £90,003
Funder: The Wellcome Trust
Recipient: University of Exeter

Aesthetics, Addictions and Health Advice: Understanding ‘Tanorexia’ in Contemporary Britain, 1978-2016 10 May 2016

This PhD will explore how the acquisition of a tan – a symbol of health and beauty in the west - has become a compulsive disorder, despite the increasing incidence and awareness of melanoma. My study will build on the factors - geographic, cultural, psychological, policy-related and economic - explored in my Liverpool based MA research, by extending to Newcastle and Blackpool (regions within these cities occupy the top nine positions - out of 324 - for the highest quantity of sunbed outlets - informed by correspondence with Cancer Research UK and Melanoma UK). This will provide a wider and deeper analysis to explain the developing and persistent high usage in sunbeds, and increasing use of tanning enhancements pills and injections.

Amount: £92,181
Funder: The Wellcome Trust
Recipient: University of Warwick
Amount: £227,598
Funder: The Wellcome Trust
Recipient: University of Cambridge

Targetting optogenetic constructs to retinal ON-Bipolar cells 30 Sep 2016

"How best can optogenetic constructs be targeted to retinal ON-Bipolar cells to restore functional vision?" This project aims to use the human photopigment melanopsin to induce light responses in retinal ON-bipolar cells (optogenetics) of a mouse model, blind from retinal degeneration, in order to restore functional vision. This comprises three key goals: Goal 1 "When" To further describe changes in bipolar cells over time during retinal degeneration in terms of their gene expression and association with other cells in the mouse model. Goal 2 "What" To determine if melanopsin - or an alternative construct (Channel Rhodopsin - ChR2) - is more efficacious in restoring functional vision. Quantified:- At a cellular level (Calcium imaging, Electrophysiology) At an organism level (Behavioural paradigms) Goal 3 "Where" To determine if bipolar cells – or an alternative target (retinal ganglion cells) - are more efficacious in restoring functional vision by melanopsin expression (quantified as in goal 2). The eventual purpose of these goals is, along with parallel work, to develop an application to the Gene Therapy Advisory Committee (GTAC) to conduct a clinical trial to restore functional vision in patients blind from inherited retinal degenerations.

Amount: £285,040
Funder: The Wellcome Trust
Recipient: University of Oxford

Establishing causal relationships from phenotypic, genotypic, and proteomic data. 30 Sep 2016

This project aims, using adrenomedullin and hypertension as an exemplar, to demonstrate the utility of using Mendelian randomisation and experimentally validated local-protein quantitative trait loci (pQTL) in combination. Local-pQTL are pQTL that map to the approximate location of their gene-of-origin. I will determine local-pQTL for the protein adrenomedullin in two isolated cohorts, one from Orkney, Scotland, and the other from Vis, Croatia. I will validate the core assumptions underlying Mendelian randomisation for one of these local-pQTL and determine, in vitro, the effects of polymorphisms at this site on ADM (which encodes adrenomedullin) gene expression and protein concentration. Finally, I will perform Mendelian randomisation in large genotyped datasets. Collectively, this will provide evidence for, or against, a causal effect of adrenomedullin on blood pressure, and represents a paradigm for assessing the causal relationships between other protein intermediates and complex traits.

Amount: £233,584
Funder: The Wellcome Trust
Recipient: University of Edinburgh

Health Priorities in Resource Limited Settings 30 Sep 2016

Liverpool Clinical PhD Programme: Health Priorities in Resource Limited Settings

Amount: £66,091
Funder: The Wellcome Trust
Recipient: University of Liverpool

Control of receptor trafficking as a therapeutic target in the inherited neuropathies. 19 Nov 2015

In this fellowship I plan to investigate whether mutations in hereditary neuropathy genes affect endosomal sorting of proteins and receptors to the plasma membrane of motor neurons and whether this leads to aberrant activation or inhibition of specific cellular pathways that can be targeted as potential therapies. In order to answer this question I will investigate a model of hereditary neuropathy due to mutations in BICD2. This fellowship has the following five aims. 1. To generate and charact erise a mouse embryonic stem cell-derived motor neuron model of neuropathy due to mutations in BICD2. 2. To analyse changes in the cell surface receptor landscape induced by mutations in BICD2. This will be performed using Stable Isotope Labelling of Amino-acids in Culture (SILAC) and mass spectrometry. 3. To validate in vitro the signalling pathways revealed in aim 2. 4. To validate in vivo alterations in the cell surface proteins identified and validated in aims 2 and 3. 5. To validate the changes in cell surface protein expression in human tissue. As almost all hereditary neuropathy mutations can impact on endosomal sorting and recycling to the cell surface, the techniques learnt during the fellowship may be applied to other forms of hereditary neuropathy.

Amount: £412,604
Funder: The Wellcome Trust
Recipient: University College London

The molecular basis of ageing in HIV infection. 19 Nov 2015

Age is the most important risk factor for most chronic diseases, but the molecular basis for the observed variation in human ageing remains poorly understood. Treated HIV-infected persons show abnormalities of many of the pathways implicated in ageing, notably persistent low-grade inflammation, mitochondrial dysfunction, and increased ROS (reactive oxygen species). Furthermore, treated HIV-infected persons show increased frailty, considered a convergent phenotype in human ageing, and predictive of adverse health outcomes. Currently however we lack an integrated mechanistic understanding of these observations, and the causal relationships remains to be established. My research goals are therefore to demonstrate: 1) that older HIV-infected persons show an excess of mitochondrial DNA (mtDNA) defects; 2) that correlates of mitochondrial dysfunction include specific anti-retroviral exposures, and that these factors show a causal association in mouse models; 3) the mechanisms (including mi tochondrial ROS production) through which these exposures may drive a mitochondrial defect; and 4) that mitochondrial dysfunction correlates with physiological decline in humans and is causally associated in mouse models. I anticipate that these experiments will both improve our understanding of the long-term complications of treated HIV infection, and increase our knowledge of the molecular basis of normal human ageing.

Amount: £419,312
Funder: The Wellcome Trust
Recipient: Newcastle University

Neural Mechanisms of Behavioural Control 05 Apr 2016

Appropriate behaviour arises from neural integration of sensory stimuli, memory of prior experience and internal states. We use genetics and the relatively small brain of Drosophila to identify conserved neural mechanisms that provide behavioural control. Recent studies located anatomically distinct synaptic junctions within the fly brain where hunger-dependent sugar memories or thirst dependent water-memories are formed by the action of distinct dopaminergic neurons. These reward-specific memories only guide behaviour when the flies are subsequently deprived of food, or water. Dopaminergic neurons also control state-dependent memory expression. We will exploit this unique cellular resolution to investigate and visualize memory formation, retrieval and extinction, and to determine how similar synaptic mechanisms allow an animal to prioritize a particular behavior over another. It is relatively easy to alter the average behaviour of a population of flies. However, considerable variance is apparent at the level of individuals. Our discovery of transposable element mobilization in the fly brain provides a plausible contributing factor to individuality. Similar LINE-1 activity in mammals suggests that transposon-generated genomic heterogeneity is a conserved feature of the brain. We will investigate neural transposition and whether it impacts the circuitry of learning and motivational control.

Amount: £3,175,224
Funder: The Wellcome Trust
Recipient: University of Oxford

Public Engagement for the Thailand Major Overseas Programme 2015 - 2020 30 Apr 2016

The mission of the Wellcome Trust Thailand Major Overseas Programme is to carry out targetedclinical and public health investigations, using the best science, to provide appropriate andaffordable interventions which produce measurable improvements in the health of resource-poorpopulations in the tropics. Over the past 35 years the Programme has built substantial clinicaland laboratory research capabilities, deployed across a well-integrated network of strategicallyplaced permanent study sites and research units in seven countries across Asia and Africa. Wewill use this expertise and research capacity to tackle the epidemiology, diagnosis,pathophysiology, treatment, prevention, and, in the case of malaria, elimination of thoseunderstudied infectious and nutritional diseases that cause significant morbidity and mortality inthe populous rural tropics. In doing so we will strengthen local research capacity, a majorobjective of the programme, and build lasting south-south research collaborations with ourpartners across the developing world. We will inform health policy, change clinical practice, andmake a global impact on mortality from tropical infectious disease.

Amount: £618,799
Funder: The Wellcome Trust
Recipient: University of Oxford

Cheers for the Beard: Victorian Facial Hair at the Florence Nightingale Museum 24 Feb 2016

The project explores the history of facial hair through time, and across different social and geographical spaces, Exploring individual British regions, as well as questions of beardedness at different social levels, it questions assumptions of elite hegemony and emulation that currently underpin existing historiography. It will recover the complex health/medical, cultural, scientific and intellectual changes that have affected views and styles of facial hair, as well as the extent to which bear ds have symbolised changing concepts of masculinity. Over the past three centuries facial hair has been closely bound with health. This study will chart various aspects from humoural views of facial hair to the beard as a visible index of health, and also its broader place within the shifting medical contexts of hair. This will include studies of medical remedies as well as the changing relationship between barbers and beards, including the eighteenth-century decline of the barber-surgeon and th e changing health and medical functions barbers undertook. It also explores the relationship between shaving technologies and the management of facial hair. Everything from cast steel to electric and disposable razors have made shaving easier, but this study interrogates the extent to which technologies directly influenced mens facial hair choices.

Amount: £30,000
Funder: The Wellcome Trust
Recipient: University of Exeter

Illuminating the brain: engineering light to monitor brain activity. 31 Dec 2015

Perinatal brain injury remains a significant cause of neonatal mortality and is associated with long-term neurological disabilities including cognitive impairment, mental retardation and accounts for 15 to 28% of children with cerebral palsy. There is an urgent clinical need to detect as early as possible those neonates at most risk and who may benefit from adjunct therapies and/or redirection of clinical care for effective rehabilitation. Early detection and assessment of brain neurological sta tus and outcome requires sensitive, robust and easy to measure biomarkers. The aims of my fellowship are to: (1) develop new methods for assessing neonatal brain injury and deliver early bedside biomarkers of atypical cognitive and neurological development; (2) inform and access efficacy of targeted interventions and clinical management for long-term neurological outcome in brain injured neonates through a clinical evaluation program. For several years now I have been developing instrumentati on and methodology that can non-invasively measure brain tissue oxygenation, haemodynamics and uniquely assess mitochondrial oxygenation through measurement of the oxidation status of cytochrome-c-oxidase (oxCCO). We have shown recently that, utilising our novel multimodal measurements that combine optics and magnetic resonance spectroscopy, in the neonatal animal model, the oxCCO measurement is a good indicator of the biochemical status of the brain and is directly related to recovery and outco me following brain hypoxic-ischaemia. This Fellowship will enable me to build upon my previous achievements and embark on an ambitious program of research to clinical evaluate and establish the brain optical measurement of oxCCO as a neuromonitoring biomarker.

Amount: £158,818
Funder: The Wellcome Trust
Recipient: University College London

The Reluctant Internationalists in the Classroom 30 Apr 2016

In the globalized world of 2011 the strengths and weaknesses of international institutions are attracting much public interest, and historians have begun to pay closer attention to the history of international collaboration. But much of this work is suffering from the limitations of local and national narratives on one hand, and a lack of appreciation of the role played bY public health on the other. This project, by contrast, constructs a new, broad perspective on ideas and forms of internation alism, and the international ambitions of doctors, medical researchers, relief workers, public health teams, politicians, generals, diplomats, and policy-makers in twentieth century Europe. Throughout the century, concerns about public health crises (real or imagined) were primary catalysts for international solutions, structures and mechanisms, which spurred or forced policy-makers at local and national levels into international action, often reluctantly. This project will examine the origins o f such policies, consequences and lasting legacies. The project will give rise to: - a major, agenda-setting monograph on the United Nations Relief and Rehabilitation Administration (UNRRA) as the most significant international organisation to be established on the ruins of the League of Nations, which significantly shaped international collaboration in its wake; - four constituent research projects on crucial international moments , regions and organisations in twentieth-century Europe, e ach resulting in a monograph and peer-reviewed articles; - a collaboratively-written popular history of twentieth century public health and internationalism; - a range of public and academic events and resources; - an international research network, led and directed from Birkbeck.

Amount: £86,976
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

Wellcome Trust Engagement Fellowship 2012. 03 Oct 2015

The Wellcome Trust is widely recognised in the UK and internationally as the leading funder of innovative public engagement, inviting the public to explore big scientific challenges. Likewise, I have a reputation and passion for delivering innovative, high-quality public engagement across the interface of science, medicine and the humanities. Public engagement has an important role in achieving extraordinary improvements in human health and, as a pioneer who works with the public, including with some of the most deprived, yet creative communities in the UK, I can offer a considerable contribution to the Wellcome Trust Vision. Through my public engagement endeavours, I work responsively to cultural contexts and strive to forge trust in order to breakdown the barriers between researchers and the public. By way of example, my public engagement endeavours have connected non-English speaking communities at risk of disease and infection to work alongside researchers investigating associated biomedical diseases. These public engagement activities have transformed community members into advocates and translators of important health information. My experience and commitment to creativity, intellectual curiosity, professional development and organisational learning ensure I thrive as a Wellcome Trust Fellow. As a filmmaker and archive fanatic I was inspired by the Wellcome Library collection, with a game, Lost Cats Legacy, that caught the attention of Sheffield International Documentary Festival. I am excited by the public engagement possibilities of the digitised material from the Wellcome Library’s collection and the prospect of support from Wellcome staff to unlock its creative potential. A Wellcome Fellowship would present considerable strategic added value by helping me to consolidate lessons from ‘networked’ and citizen-led approach to public engagement that I am pursuing. Specifically I will offer an offering ongoing legacy to support the Trust’s Vision through audiences reached, quality of partnerships and heightened profile of biomedical science.

Amount: £826
Funder: The Wellcome Trust
Recipient: Squirrel Nation Limited

“Balint Groups” and the Patient-Doctor Relationship: The Social History of a Psychoanalytic Contribution to the Medical Sciences 11 Jan 2016

The project studies the emergence of "Balint groups", initiated by the medically trained psychoanalyst Michael Balint in the 1950s. In the groups, psychoanalysts encountered medical doctors to discuss the latter’s difficulties with their patients. This encounter has unexplored consequences for the understanding of illness and the formation of medical doctors. I propose a multi-method social history of "Balint groups" and I ask two questions: how can we understand this complex psychoanalysis-medicine conversation and what does this case have to say about what psychoanalysis can offer to medicine, with respect to making sense of illness? The project has four dimensions of research: theoretical, examining Balint’s innovative relational conception of illness; historical, analysing the importance of Balint’s embeddedness in the Budapest School of psychoanalysis; epistemological, looking at the forms of boundary-work between psychoanalysis and medicine that characterised the emergence of Balint groups and reflecting on the collective and transdisciplinary knowledge produced in the groups; ethical, discussing the non-hierarchical modes of relationality in the groups. The project relies on archival research and brings to light the novel material contained in the Balint Archive, held by the British Psychoanalytical Society since 2014. The research will also involve in-depth interviewing of psychoanalysts and medical doctors.

Amount: £195,829
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

The impact of policies that aim to reduce child poverty on child and maternal mental health and health inequalities 13 Jan 2016

UK child and maternal mental health is poor, with large inequalities between socioeconomic groups. High child poverty rates are a key factor, yet limited evidence exists for how welfare policy changes targeting child poverty impact upon child and maternal mental health and associated inequalities. Policy changes might have adverse or beneficial effects; through direct impact on poverty or indirectly, by increasing employment or more punitive welfare regimes. This project will investigate the effect of changes to the tax credit system on child and maternal mental health from 2000-2016, using innovative methodologies for evaluating natural policy experiments. Goals include; developing a conceptual framework to assess the impact of policy changes over time; measuring the influence of policy on the level, eligibility, and uptake of tax credits across social groups over time and; developing statistical methods for analysing large longitudinal datasets to investigate causal effects of policy changes on income, poverty, and mental health of mothers and children. Findings will expand understanding of policies changes, and how modifying these can reduce mental health inequalities. Engagement with academics, policy makers, and organisations working with low-income families will maximise the research impact. Key words: child and maternal mental health; poverty; policy; tax credits; inequality

Amount: £211,199
Funder: The Wellcome Trust
Recipient: University of Liverpool

Clinical Genomic Medicine and the Need for a Public Health Ethics Account 13 Jan 2016

The implementation and practice of clinical genomic medicine increasingly employs a population perspective in the utilisation of data and the integration of genomics within healthcare systems. However, the contemporary accounts of ethics and genomics tend to lag behind, focussing primarily on the best interests of individuals and their families. These ethical accounts are unsuited to addressing the new ethical problems resulting from the population approach in clinical genomic medicine e.g. the use of population level data sets to interpret variants of unknown significance. Might an account built upon public health ethics, which tends to emphasise the balance between protecting and promoting the health of populations, whilst avoiding individual harm, be more suited to the assessment of clinical genomic practice? This research will explore whether public health ethics can offer a more fitting and practical account for the ethics of clinical genomic medicine. The key research goals include combining empirical and normative analysis of public health ethical values for application in clinical genomic medicine, the formulation and dissemination of practical guidance and useful recommendations for application in clinical genomic medicine policy and practice. The methodology employed will involve conceptual ethical analysis and qualitative interviews with key stakeholder groups in the UK.

Amount: £289,647
Funder: The Wellcome Trust
Recipient: University of Oxford

Resisting depression stigma: exploring complementarities and contradictions 13 Jan 2016

Whilst depression itself represents a significant and growing global public health issue, so too does the stigma associated with it, given that people so diagnosed frequently experience and anticipate high levels of discrimination across the world. To date, however, there is limited knowledge about effective strategies to combat stigma related to depression. Problems with stigma concepts complicate this, too, as dissimilar processes, experiences and phenomena can constitute 'stigmatisation', with the consequence that 'stigma resistance' denotes diffuse and contradictory practices across governments, institutions, groups and individuals. This presents significant problems for people diagnosed with depression, carers, policy makers, advocacy experts and medical professionals across the world. How might they best proceed on the issue of depression stigma reduction? The main aim of this three-year sociological study is to address this problem through three interlinked research components that seek to explore complex anti-stigma discourses and practices, ultimately providing evidence which will inform future strategies and concentrate resources. To do this a heuristic of social scales is invoked, which distinguishes ‘global’, ‘national’ and ‘local’ practices. Whilst interweaved in reality, these ‘scales’ provide novel ways through which anti-stigma enactments can be explored. Together they constitute a ‘multi-sited ethnography’ of stigma resistance.

Cataloguing original archival material at the Freud Museum 30 Sep 2016

The Freud Museum has 28 boxes of archival material that has been donated since the Museum opened but remains uncatalogued. This is valuable material that is in urgent need of cataloguing. It includes, for example, boxes of items from: Josefine Stross, Sigmund Freud’s physician; Dorothy Burlingham, Anna Freud’s lifelong companion; Lux Freud, Lucian and Clement’s mother; and Jula Weiss, Anna Freud’s secretary and assistant. Currently these collections are not even listed and so we would like to catalogue these to best practice standards, as recommended by the Wellcome-funded consultant Judith Etherton as a result of the scoping grant in 2013 (attached to this application). We will then put the catalogues online. This will complete the cataloguing of the Freud Museum archives, and make them more accessible to researchers worldwide.

Amount: £17,929
Funder: The Wellcome Trust
Recipient: Freud Museum London