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The Wellcome Trust

Results

The biology of acute myeloid leukaemia 30 Sep 2016

Mutations in epigenetic regulators play a pivotal role in leukaemia initiation. We propose to study the most commonly mutated epigenetic regulator in AML: the de novo DNA methyltransferase DNMT3a (25%). It is unclear how DNMT3a mutations subvert HSC, surprisingly in bulk studies differences in methylation do not correlate with differences in gene expression, but somehow DNMT3a mutated HSC have an advantage in xenografts and survive apparently successful chemotherapy in 80% of patients. Even if a persistent clone does not predict relapse rate these patients tend to have a poorer prognosis. DNMT3a mutations are also the most prevalent in individuals with "clonal haematopoiesis". To study DNMT3a mutated preleukaemia we will use a mouse model where the most common DNMT3a mutation (R882H) and an RFP are under the control of the Mx1-cre promoter. By titrating the dose of pIpC we will generate a chimeric mouse where only ~ 20% of cells express the mutant allele. We will study clonal dynamics after challenging HSC homeostasis (through lineage tracing of the RFP) and document alterations in gene expression at the single cell level at baseline and after perturbing HSC using state-of-the-art technology (Polaris system). We will then corroborate our findings in human DNMT3aR882 preleukaemia.

Amount: £252,167
Funder: The Wellcome Trust
Recipient: University of Cambridge

Investigating the phenotype, function and interactions of tissue-resident B cells 30 Sep 2016

Tissue-specific immunity is shaped by the local milieu. In organ systems that interface with the environment (e.g. skin, gastrointestinal tract), exogenous signals generated by commensals or diet can profoundly influence resident immune cells. In non-interfacing tissues (e.g. kidney), endogenous signals such as interstitial osmolality may also influence the immune landscape. Tissue epithelial cells play an important role as environmental sensors and may instruct local immune responses. In addition, environmental cues may be directly detected by resident immune cells. To date, studies of tissue sentinels have focused on innate immune cells and on T cells with limited data on B cells. We have preliminary data from human and murine kidneys, and from human liver tissue and murine bladder tissue demonstrating the presence of tissue-resident B cells. In humans, they are predominantly of a memory phenotype. We hypothesize that tissue-resident B cells make an important contribution to local immune responses and that their localization and function will be determined by tissue-specific environmental cues. This project aims to investigate the phenotype of these tissue resident B cells (both in mouse and human), their antigenic specificity, origin, function and interaction with other cells.

Amount: £235,304
Funder: The Wellcome Trust
Recipient: University of Cambridge

The Role of the Adaptor Protein-2 Sigma Subunit (AP2σ) in Calcium Homeostasis 30 Sep 2016

G-protein coupled receptors (GPCRs) facilitate cellular responses to extracellular stimuli, and GPCR mutations result in many diseases, including endocrine disorders. Mutations of the calcium-sensing receptor (CaSR), a pivotal GPCR in calcium homeostasis, resulting in loss-of-function or gain-of-function cause familial hypocalciuric hypercalcaemia type-1 (FHH1) and autosomal dominant hypocalcaemia type-1 (ADH1), respectively. FHH and ADH are genetically heterogeneous, and loss-of-function or gain-of-function mutations of the G-protein-alpha11 utilised by CaSR, cause FHH2 and ADH2, respectively; while loss-of-function mutations of adaptor protein-2 sigma subunit (AP2sigma), which is critical for clathrin-mediated endocytosis, cause FHH3. To date, the reported AP2sigma mutations, which cause only FHH3 but not ADH, all affect residue Arg15 and impair CaSR signalling and trafficking. However, the Thakker group have recently identified seven other AP2sigma variants (Arg3His, Ala44Thr, Phe52Tyr, Arg61His, Thr112Met, Met117Ile, Glu120Gly), and my goal is to determine the roles of these AP2sigma variants in calcium homeostasis by: 1) Characterising their structural-functional relationships by in vitro studies that assess effects on three-dimensional models and on CaSR signalling and trafficking pathways. 2) Determining in vivo phenotypes of AP2sigma mutations by generating knock-in mouse models, using CRISPR-Cas. 3) Assessing pharmacological effects of drugs, e.g. velcalcetide, using above AP2sigma in vitro and in vivo models.

Amount: £348,449
Funder: The Wellcome Trust
Recipient: University of Oxford

Hepatitis B in Malawi: Epidemiology and determinants of fibrosis and virological expression 30 Sep 2016

Hepatitis B (HBV) is highly endemic in Malawi with an estimated seroprevalence of 7.5 (95% confidence interval 5.5-10.6). Among a recently described HIV/HBV co-infected cohort in Blantyre, particularly aggressive virological expression was observed compared to other sub-Saharan African cohorts, with high rates of HBV replication, HBe antigen expression, and poor responses to lamivudine. There are very limited data on the epidemiology and natural history of HBV from sub-Saharan Africa. Current understanding of the environmental, viral and host factors responsible for determination of disease severity are derived largely from Asian and Western cohort studies. The aim of this project is to determine the determinants of severity of HBV among a community study in Blantyre, Malawi. Random adult participants in an observational community-based study of typhoid seroincidence (n=9700) will be screened for HBsAg and 250 positive and 125 negative controls will be recruited. An inpatient cohort of people with liver disease will also be screened for HBV. Markers of HBV virological expression, transient elastography to determine liver fibrosis, questionnaires for lifestyle factors and next generation genome sequencing of HBV and host will be undertaken to determine the relative contribution of environmental, host and viral genetic factors to the development of fibrosis.

Amount: £400,000
Funder: The Wellcome Trust
Recipient: University of Liverpool

Respiratory Gene Therapy Portfolio (RGTP) 10 Dec 2015

Gene therapy aims to treat diseases by delivering genes that produce therapeutic proteins. Over two decades the UK CF Gene Therapy Consortium (GTC) has pooled the resources of three major groups in the UK (Oxford and Edinburgh Universities and Imperial College London), progressing from laboratory studies to the first demonstration that gene therapy can produce improvements in the lungs of CF patients. The key steps forward have been a) to identify methods by which genes can be delivered into the lungs and b) the understanding that the new genes can secrete proteins both into the lungs and blood stream. The GTC's underpinning platform technology for the Portfolio is a viral gene therapy platform based on the rSIV.F/HN lentiviral vector which will be applied to five projects: Influenza A- a major worldwide health risk causing >500,000 deaths each year. Primary Ciliary Dyskinesia (PCD) - a life-threatening recessive condition, it has a worldwide incidence of -1/10000. Alpha 1 Anti Trypsin Deficiency (AATD)- rare genetic disease which is present in almost all ethnic groups. Worldwide there are estimated to be -200,000 patients with AATD. Haemophilia - affects around 400,000 individuals worldwide, of whom 85% have Haemophilia A (Factor VIII deficiency) and 15% Haemophilia B (Factor IX deficiency). Surfactant Protein B (SP-B) deficiency- one of several rare interstitial lung diseases that cause alveolar collapse and respiratory distress syndrome (RDS) in newborn babies. Due to the lack of donor organs, and the unstable state of the disease, lung transplantation is rarely attempted and the majority of individuals affected by SP-B deficiency succumb to the disease within the first few months of life.

Amount: £6,402,078
Funder: The Wellcome Trust
Recipient: Imperial 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

Epigenetic inheritance: establishment and transmission of specialised chromatin domains 05 Apr 2016

Specialized chromatin domains provide platforms that mediate fundamental cell and developmental functions. The histone H3-variant CENP-A chromatin directs assembly of kinetochores at specific chromosomal locations to enable accurate chromosome segregation. Heterochromatin renders potentially harmful repetitive elements inert and silences genes during development. Regional fission yeast centromeres provide an excellent paradigm for unwieldy metazoan centromeres. Our analyses indicate that H3K9-methylation-dependent heterochromatin and CENP-A assemble upon non-conserved elements at centromeres whose chromosomal location is preserved in related Schizosaccharomyces species. My predominant goal is to understand the conserved signals and mechanisms that distinguish these non-conserved centromere sequences from other genomic loci, as well as the epigenetic mechanisms that result in the establishment of heterochromatin and CENP-A chromatin, and their stable mitotic and transgenerational transmission. I aim to determine: 1. How specific signals associated with centromere DNA, RNA, chromatin and RNAPII transcription direct assembly and maintenance of heterochromatin and CENP-A specialised chromatin domains. 2. The influence that positioning at the nuclear periphery exerts on heterochromatin domain robustness and the establishment of CENP-A chromatin on adjacent centromere DNA. 3. The potential for sporadic heterochromatin formation across the genome to generate phenotypic heterogeneity in genetically identical wild-type cells thereby increasing adaptability to environmental changes.

Amount: £3,046,873
Funder: The Wellcome Trust
Recipient: University of Edinburgh

Advancing cognitive therapy for anxiety disorders and PTSD 05 Apr 2016

The proposed research addresses two of the major problems in psychotherapy research: How can effective psychological treatments be made available to the large number of people with mental health problems? and How can researchers make rapid progress in making the treatments even more effective? The applicants have developed leading psychological therapies for three anxiety-related disorders (social anxiety disorder, posttraumatic stress disorder and panic disorder). They now propose to harness the power of the internet to solve both problems. Internet-delivered versions of the treatments will be developed and evaluated that require much less therapist time and can be delivered anywhere. Dissemination and evaluation of the treatments within NHS Improving Access to Psychological Therapies (IAPT) services will create a large database that will enable rigorous study of moderators and mediators of therapeutic change to identify targets for further improvements. Modifications of the treatment will then be evaluated in experimental treatment studies. The work will help realise the population level mental health benefits of previous Trust investment in psychological therapy research and align with the Trust’s new focus on maximizing the application of research to improve health by focusing on new product development and the uptake of patient-oriented research advances.

Amount: £3,266,571
Funder: The Wellcome Trust
Recipient: University of Oxford

Wellcome Trust Engagement Fellowship 20 Jul 2016

Founded in 2010, Touretteshero has one ambition: to change the world one tic at a time. This simple, yet radical proposition informs our philosophical, artistic and practical approach to making creative work and engaging diverse audiences with ideas relating to disability. Our shared vision of the future is for: A society in which assumptions about difference are transformed into constructive conversations Negative narratives around disability that feed entrenched stereotypes dominate our cultural landscape. This is damaging to both disabled and non-disabled people and means that opportunities to understand wide-ranging experiences are lost. Research by social scientists relating to disability rarely pierces public consciousness, and this means opportunities to challenge perceptions and broaden the conversation are often missed. A report by Scope in 2014 found that, "67% of the British public feel uncomfortable talking to disabled people". This is a statistic that we aim to address in our vision for the future. Cultural, scientific and public spaces in which disabled people are visible and included equally Census data from 2011 shows that 18% of the UK population identify as being disabled. Yet this is not reflected amongst those leading our arts, public, and academic sectors. Diversity statistics published by three leading bodies – the Arts Council, Higher Education Statistics Agency and Civil Service – show that disabled people make up just 2% of the workforce in major arts institutions, 6% of those working in the civil service, and just under 4% of academic staff in our universities. This is significant because it means that the ideas and experiences of disabled people will not be present within the institutions shaping our culture, thinking, and policy implementation. This represents a risk for us all because it means that disabling barriers are likely to remain invisible, particularly to those in influential positions. A society that is inclusive and responsive to all In 2011 World Health Organisation Director Dr Margaret Chan said, "Almost every one of us will be permanently or temporarily disabled at some point in life. We must do more to break the barriers which segregate people with disabilities, in many cases forcing them to the margins of society." Our vision is for a future in which disabled people play an equal role in society and where inclusive approaches are embedded within our communities ensuring that an individual’s needs or circumstances can change without their whole life needing to change as well. Communities that are curious, questioning and engaged and have a deepened understanding of themselves Our aim is for a future in which access to ideas, and opportunities to think about, discuss, and challenge them, are accessible to everyone. Academic and scientific Research can sometimes seem abstract or out of reach to those impacted by the issues being investigated. In our vision of the future there is a more fluid, collaborative connection between research and patient communities. The theories and knowledge generated by researchers become springboards for shared discussion, action and increased understanding.

Amount: £256,000
Funder: The Wellcome Trust
Recipient: Touretteshero CIC
Amount: £30,000
Funder: The Wellcome Trust
Recipient: No Organisation

The demand for prevention in middle and later life 18 Jul 2016

Population ageing is likely to increase the burden of non-communicable diseases (e.g. cancer). Prevention (including health behaviour and screening programmes) can considerably reduce the morbidity and mortality risks of these diseases, and will therefore play a key role in maintaining the health of an ageing population. The research project will investigate the demand for prevention among middle-aged and older people theoretically and empirically. In the first part of the project, I will derive a theoretical framework based on the health capital model that allows me to derive hypotheses on determinants of the demand for prevention, in particular with respect to time costs. In the empirical part of the project I will test these hypotheses using econometric methods for causal inference and data from the UK as well as international data. I will analyse three specific factors that are associated with different levels of time costs and play a major role among older people – retirement, informal care provision and voluntary work. The projected output will consist of at least four academic papers and a number of conference presentations. I will engage members of the public in an advisory group. Keywords: prevention, screening, health behaviour, causal inference, ageing

Amount: £176,150
Funder: The Wellcome Trust
Recipient: University of Oxford

Patient and public involvement in priority setting: should we listen to the will of the people? 13 Jan 2016

Decision-makers tasked with allocating resources within health systems often face huge pressure about funding decisions from patients and the public, often described as lobbying. One question that we may want to settle is how far particular priority setting decisions are influenced by lobbying and lobbyists. However, we might also ask another, ethical question: namely, to what extent should priority setters respond to political pressure when making decisions about the allocation of health care resources? In this project, I aim to provide a detailed philosophical analysis of how far decision-makers ought to respond to attempts by patient and public interest groups to influence priority setting decisions through lobbying and other forms of political pressure. The project will use an ‘empirical ethics’ approach, combining both philosophical analysis and qualitative research. Overall, the research is intended to achieve two primary goals: 1) To give a robust ethical analysis of priority-setters moral obligations to respond to, or act upon, lobbying and other kinds of political pressure by patients and the public when making decisions about how to allocate health care resources. 2) To give concrete practical advice to such decision-makers on how they ought to respond to lobbying in the future.

Amount: £149,624
Funder: The Wellcome Trust
Recipient: University College 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

Glamorgan's Blood: Dark Arteries, Old Veins - Cataloguing and Conserving the Records of the National Coal Board 18 May 2016

1) Employ an archivist on a 3 year project to: Reconstruct the pre-vesting records of private companies Catalogue the National Coal Board (NCB) records, including: sorting and appraisal renumbering repackaging creation of new catalogue descriptions enhancement of existing descriptions updating of lists in word/excel formats and their transfer into CALM imposition of clear structure and arrangement consistent numbering system address records series which began prior to nationalisation and continued afterwards 2) Employ a conservator on a 2 year project to: Establish conservation priorities Identify the plastic material of which many of the plans are made Carry out remedial conservation Flatten folded / rolled items Address storage requirements of newly flattened items Plan for future digitisation of unusable material Supervise and train staff and volunteers to: Repackage the collection Repackage glass plate negatives Clean volumes 3) Dissemination Promotion of the project through social media Press coverage Contribution to Glamorgan Archives (GA) annual events programme Closing event Body of work produced: Full item level catalogue of NCB records and those of pre-vesting date companies Collection stabilised and repackaged to ensure future preservation Discoverability and accessibility of collection disseminated to potential audiences, including the general public along with the academic community.

Amount: £203,456
Funder: The Wellcome Trust
Recipient: Glamorgan Archives

Inside Medical Science: Conversations with Experts 18 May 2016

Oxford Brookes University is the custodian of the Medical Sciences Video Archive, a collection of 287 video recorded interviews with prominent figures in medicine created between 1985 and 2002. The collection is unique and represents the only recorded interviews with prominent figures from medical science, including a selection of Nobel Prize winners. At present the collection is trapped in legacy formats that do not allow for wider dissemination and use. The University proposes to digitise the recordings and make them openly available on the web. The imperative for digitising the collection is driven by two factors; increasing access to the recordings, and enabling their long-term preservation. Digitisation will address both of these issues, ensuring that the materials have as wide an impact as possible, and guaranteeing their on-going preservation beyond the life of the current physical media on which they are stored. The collection will be made available online, with no restrictions on access, via Oxford Brookes University's Research Archive and Digital Asset Repository (RADAR). A dedicated collection and associated web pages will be created. Long-term preservation, curation and secure storage of the digitised collection will be delivered by the Arkivum service currently in use at Oxford Brookes University.

Amount: £38,801
Funder: The Wellcome Trust
Recipient: Oxford Brookes University

Cataloguing and Preservation of the Whitehall Study 25 Nov 2015

In 1967, LSHTM began its major Health Survey of Male Civil Servants aged 40 or over. This is widely referred to as the Whitehall Study. The study was the first to draw attention to important links between lifestyle, particularly smoking, inherited risk factors and subsequent disease. It found significant differences in life expectancy between civil servants on administrative grades and those in lower positions, basically the lower the grade of employment, the higher the death rate from all of the major causes of death. This was a crucial finding for establishing a link between social status and health, and the Whitehall study thus occupies a key place in the history of debates about the social determinants of health. The collection comprises of raw data and administrative papers from the original study, as well as follow-up papers from the 1970s. The collection will be catalogued according to international standards, repackaged in preservation materials, and conservation measures will be undertaken as recommended in the 2012 Wellcome Trust funded Scoping Study reports. The resulting descriptions will be made available to the medical history community via the Archives Service online catalogue, and publicised through a range of dissemination activities.

Scoping the Royal Hospital for Neuro-disability archives 30 Sep 2016

This is a scoping project intended to ascertain the cultural value of the RHN's historic archive. The archives have only been established and developed in the last 4 years but contain records dating back to the founding of the hospital. These records have never been fully assessed. The records have also never been previously available to the public or to researchers. The key goals of this project are: 1) assessment of the archive by a professional archivist 2) assessmnet of the archive by a professional conservator 3) creation of a report by archivist and conservator regarding the contents and condition of the archive materials. We believe that the archive materials at the RHN hold significant value for the local community as the hospital has existed in this location for over 150 years and has been a major employer in the local area. Further we also believe that the archives, particularly the medical records, hold great value for researchers interested in medical and social history.

Amount: £4,355
Funder: The Wellcome Trust
Recipient: Royal Hospital for Neuro-Disability

Stoke Mandeville: Path to the Paralympic Games 30 Jan 2016

This application for a scoping study is part of a collaboration between the Centre for Buckinghamshire Studies and the National Paralympic Heritage Trust on a wider programme of work. The archives in question have recently been at risk, and we have already worked to remove them from inadequate storage and move them to the recognised place of deposit for public records in Bucks, thus saving this sensitive material from deterioration. The collections have national and international significance. The National Spinal Injuries Centre has led the way in the care of people with spinal injuries from the 1940s to date. Sir Ludwig Guttmann was an international pioneer and his work is still used today - both through the treatment of spinal injuries, and also through psychology, the use sports as rehabilitation, and the invention of specialist equipment. We have an immediate need to scope what is required for cataloguing and conservation - these collections are a new area of collecting for us and have specialist academic and medial research potential, which is not an area of expertise for CBS. The reports that are to be produced as part of the study will feed into a further application for the work.

Amount: £10,875
Funder: The Wellcome Trust
Recipient: Buckinghamshire County Council

Scoping Study for Bristol's Board of Health Building Plans Archive 29 Feb 2016

Building development in Bristol from the mid-nineteenth century onwards was underpinned by concern for the health of its citizens. In an effort to stem outbreaks of cholera, all plans for new buildings were submitted to the City Engineer in order to satisfy new legislation for the provision of clean water and sewerage. The plans provide a detailed account of Bristol’s rapid expansion, and as a historic collection they are unique; no other comparable British city has such a full set of architectural building plans. However, this extraordinary record series, which was never originally conceived as an archival collection to be kept in perpetuity, has become extremely fragile and is now in danger of being lost. The funding will enable Bristol Record Office to commission an external consultant archivist and archive paper conservator to produce a scoping report that examines the potential of the collection for future research, and makes recommendations as to how best the plans can be preserved and continue to be made accessible through conservation and digitisation work. The report represents the first stage in the development of a long term programme of work that will ensure the plans' future survival.

Amount: £8,600
Funder: The Wellcome Trust
Recipient: Bristol City Council