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Recipients:
University of Oxford

Results

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

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

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

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

Capture NanoporeSeq: A novel technique for targeted full-length transcript sequencing and gene expression analysis 08 Apr 2016

The accurate characterization and quantification of expressed gene isoforms is essential to understanding how genetic variation affects gene expression and ultimately disease risk. However, the expressed isoforms identified by standard RNA sequencing methods are often incorrect due to the near ubiquitous presence of alternative gene isoforms in the human transcriptome. This project aims to address this problem by developing a novel technique (Capture NanoporeSeq) to perform full-length cDNA sequencing of target human genes and so unambiguously identify which isoforms are expressed. Capture NanoporeSeq will combine Oxford Nanopore long-read sequencing, which can sequence full-length cDNAs, with targeted RNA sequencing (CaptureSeq), which will provide high sensitivity for targeted gene isoforms. Once developed, Capture NanoporeSeq will be validated in post-mortem human brain tissue to identify and quantitate the expression of gene isoforms from genomic regions linked to neuropsychiatric disorders. Capture NanoporeSeq will significantly improve our ability to accurately characterize and quantify gene expression. This will be of immediate use in neuropsychiatric disease genetics where many risk genes have lowly expressed disease-linked isoforms and/or complex splicing patterns, helping to illuminate the impact that disease-associated genetic variation has on gene expression.

Amount: £86,822
Funder: The Wellcome Trust
Recipient: University of Oxford

Compartmentalisation via liquid-liquid phase separation in cells 01 Jun 2016

Cells spatially and temporally isolate molecules in subcellular compartments to both facilitate and regulate their interactions. In addition to organelles formed by membrane-encapsulation, cells possess membraneless organelles such as nucleoli, Cajal bodies, stress-granules and nuage. These bodies are highly dynamic, and rapidly assemble and dissolve following changes in the cellular environment and cell cycle. They are predominantly associated with nucleic acid biochemistry, and have been linked with neurodegenerative diseases and viral infection. Membraneless compartments typically display the properties of liquid droplets, and form by phase separation of disordered and multivalent proteins, making them exceedingly difficult to isolate and study. By reconstituting model membraneless organelles in cells and in vitro, I have taken significant steps towards characterising their properties. My research shows that their interior solvent environment is distinct from the bulk water in the cell, capable of localizing proteins and nucleic acids, and modulating their structure. However, the biochemical consequences of performing reactions in such environments are unexplored. I propose to use an interdisciplinary approach to explain how liquid-liquid phase separation provides a general organizing principle in cells, and study how the internal organelle environment influences biochemical reactions performed by helicase, nuclease and polymerase enzymes.

Amount: £1,152,782
Funder: The Wellcome Trust
Recipient: University of Oxford

Functional and computational analyses of the regulation of glucagon secretion in health and disease 19 Apr 2016

In type-2 diabetes mellitus (T2DM), pancreatic beta-cells fail to secrete insulin in response to high blood-glucose concentrations. However, in many diabetic patients, glucagon secretion from pancreatic alpha-cells is also impaired; glucagon secretion fails to be suppressed by high blood-glucose, and fails to increase even when blood-glucose falls to dangerously low levels. This impaired ‘counter-regulation’ in diabetes is a major cause of mortality in insulin-treated patients. The mechanisms underlying the glucose control of glucagon secretion from alpha-cells remain poorly understood, even under healthy conditions. There is conflicting evidence that at least four different ion channels contribute to the normal counter-regulation of glucagon secretion, as well as evidence for external paracrine influences. In this project, I will investigate the ion channels that contribute to the normal counter-regulation of glucagon secretion from alpha-cells by using pharmacological and electrophysiological techniques in KO strains of mice. I will combine this with computational modelling of alpha-cells; the models will help me to verify my experimental findings and understand which mechanism(s) could explain the impaired counter-regulation seen in T2DM. I will then investigate the findings of the model in an experimental (mouse) model of T2DM as well as by recording from human islets from T2DM donors.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Determining how distinct vertebrate promoter classes coordinate cis-regulatory input. 11 Nov 2015

Highly coordinated gene regulation is essential for multicellular development and when perturbed can lead to disease. Normal transcriptional regulation relies on communication between gene promoters and distal regulatory elements (DREs)[9,10], a process that appears to involve extensive interactions between these sites[11-13]. However, the mechanisms driving these interactions remain poorly understood, limiting our capacity to fully understand gene regulation. In order to bridge this major conce ptual gap, I will use cutting-edge genomic and evolutionary approaches to determine how promoters engage with their respective DREs. This will be achieved by focussing on the two major vertebrate promoter types, CpG-rich and CpG-poor, and detailing promoter/DRE interactions in mouse embryonic stem cells. I will then genetically perturb CpG-rich promoter chromatin to determine how chromatin architecture contributes to the establishment of these interactions. Building on this work, I will identify promoter/DRE contacts in related yet divergent vertebrate species to understand how interactions form and are affected by genomic arrangements during evolution. This ground-breaking study will provide novel insight into how promoter type, chromatin architecture and genomic organisation contribute to promoter/DRE interactions, significantly advancing our understanding of gene regulation.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Metabolic control of T cell receptor signalling 11 Nov 2015

T cell receptor (TCR) activation is essential for the effector functions and proliferative potential of T lymphocytes. Optimal TCR responsiveness requires assembly of the TCR signalosome, a super-molecular signaling complex that couples external antigenic cues to intracellular biochemical events. I discovered that spontaneous activation of the metabolic master regulator AMPK induces loss of the TCR signalosome from human senescent T cells, a novel hallmark of human ageing. This suggested the exi stence of an unrecognized link between changes in T cell metabolism and TCR responsiveness. I also identified cross-talk between AMPK and p38 MAPK signaling that regulates both senescent features and metabolic demands of T cells. Whether intervention at the point of energy sensing pathways may restore TCR functional activity in senescent T cells is not known. Here I propose that the modulation of metabolic pathways by disrupting the AMPK-MAPK signaling axis would restore TCR function. Restoring TCR responsiveness in senescent T cells would offer novel ways to recover T cell activity among the elderly population that suffers from increased susceptibility of opportunistic infections and cancer. Furthermore, since T cells undergo metabolic impairment during an immune response, these studies may have relevance for boosting non senescent T cell responsiveness in vivo.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Workshop: Human evolution in structured populations 30 Apr 2016

Understanding the origins and early demographic history of our species has wide ranging implications for the medical, social and biological sciences. Until recently, consensus for a single East African centre of endemism for Homo sapiens was widespread. However, archaeological, fossil and genetic data increasingly suggest that the emergence of our species occurred within a set of subdivided populations located across Africa, rather than within a small and isolated East African population. The complexity of our origins is further emphasised by admixture with archaic Homo species in Eurasia and possibly even in Africa itself. This notwithstanding, competing models of ours origins remain to be evaluated within an interdisciplinary context invoking evidence for intra-African dispersals, population size and structure. Instead, research on the origins and early demographic history of Homo sapiens remains frustratingly disjointed, with often-incompatible jargon and methods of data analysis. In this workshop, archaeologists, geneticists, palaeoanthropologists and related specialists will forge integrated, interdisciplinary models explaining the often-contradictory evidence gleaned from different sources of data. The workshop will begin with a public symposium followed by two days of discussion and debate, permitting the development of a new, integrated data hypotheses of the processes culminating in today’s cultural and biological diversity.

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

Structural insights into the link between GATA2 and acute myeloid leukemia (AML). 01 Apr 2016

Acute myeloid leukaemia (AML) is a blood-related disease characterised by the uncontrolled proliferation of haematopoietic stem cells lacking the ability to commit to normal differentiation. It is highly malignant, with only a 25% survival rate 5 years after diagnosis, despite intensive therapeutic treatments. GATA2 is a zinc-finger (ZnF) transcription factor broadly expressed in haematopoietic stem cells (HSCs). GATA2 is necessary for maintenance of a regenerative HSC pool as well as lineage-restricted differentiation. Given this, it is perhaps unsurprising that GATA2 mutations have been linked with AML. Currently, little is known about the mechanism of GATA2 function in leukaemias. GATA2 contains 2 ZnF domains (NF and CF), which have been shown to bind different DNA motifs and protein partners in vivo. I postulate that these interactions are necessary for the biologial activity of GATA2, and will attempt to show that mutations in the NF and CF domains result in loss of this activity. This will be achieved by using a combination of methods including bioinformatics, molecular docking and in vitro biophysical studies using generated GATA2 mutants. This research aims to show that GATA2 mutants deregulate HSC proliferation by virtue of altering its ability to interact with cognate partners.

Amount: £2,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Structural insights into the Rifin protein family of the malaria parasite 01 Apr 2016

Members of the RIFIN family of Plasmodium falciparum are expressed on the surfaces of infected erythrocytes, where they are one of the few surface protein families exposed to the host immune system. They are members of a broader protein family, including the stevors, virs and pirs that are expressed across malaria parasites. This project aims towards the structure of the extracellular domain of a rifin protein, which will allow us to understand the architecture of this entire family of proteins. It also aims to understand the molecular basis for the interaction of a rifin with a novel class of antibody molecule with a LAIR1 insertion and to the molecular basis for the interaction of a rifin with a blood group A antigen. These studies will help us to understand the role of this enigmatic Plasmodium surface protein family that have been implicated in disease severity.

Amount: £2,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Modelling the evolutionary epidemiology of chronic viral infections: Incorporating host heterogeneity into nested models of virus evolution 01 Apr 2016

One of the principal challenges in epidemiology is using mathematical models to plan disease control. This is made more challenging by pathogen evolution, which increases the complexity of disease dynamics, acting as a barrier to effective control. Chronic viruses such as HIV exhibit evolution over significantly shorter timescales than the long duration of infection. Understanding pathogen evolution and including it in models is therefore a key challenge for mathematical biologists. This project will explore how heterogeneity between hosts affects evolutionary dynamics at the population scale, building on a model in an existing paper that assumes that all hosts are identical. In this project, the model will be extended to include the heterogeneous immune responses to infection observed in different individuals. The dynamics of this new model will then be compared with the model in which all individuals are identical. Mathematical techniques required for this project include analysis of integro-differential equations (such as calculation of equilibria) and examination of the behaviour of integro-differential equations via numerical solution. The key goal is to develop a model of virus evolution that includes heterogeneous host types, and to investigate the evolutionary behaviour predicted by the model with different extents of host heterogeneity.

Amount: £1,750
Funder: The Wellcome Trust
Recipient: University of Oxford

Thailand Major Overseas Programme core grant renewal 2015-2020. 21 Apr 2015

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: £14,698,261
Funder: The Wellcome Trust
Recipient: University of Oxford

Viet Nam Major Overseas Programme core grant renewal 2015-2020. 21 Apr 2015

Our vision for the Viet Nam Major Overseas Programme is to perform world-leading clinical research with a major impact on local and global health. We will lead a research-driven response to the major and rapidly evolving challenges to healthcare in Asia. We will build regional scientific capacity through a unique and synergistic network of research units, led by the Oxford University Clinical Research unit in Ho Chi Minh City and Hanoi, Viet Nam, and incorporating the Eijkman-Oxford research unit in Jakarta, Indonesia, and the Patan-Oxford research unit in Kathmandu, Nepal. After a decade of development and research diversification, the programme will place emphasis on increasing the impact of our science, the quality of our research, and the efficiency of our operations. Our core research themes will make defining contributions to the understanding of infectious diseases transmission and susceptibility; will develop new tools to prevent, control and treat antimicrobial resistant organisms; will improve clinical outcomes of the major endemic and emerging infectious and non-infectious diseases; and will enhance public health policy in the region. Our unparalleled network of units, partnerships and collaborations, developed over time and spanning every level, enable us to remain ambitious and to deliver world-class research across these themes.

Amount: £16,671,343
Funder: The Wellcome Trust
Recipient: University of Oxford

Improving the management and prevention of tetanus in Vietnam. 13 Apr 2015

Key Goal 1. To establish whether intrathecally administered antitoxin reduces the requirement for mechanical ventilation, and in addition reduces mortality, duration and cost of intensive care unit stay, duration of mechanical ventilation, requirement for antibiotics, and incidence of predefined nosocomial infection and autonomic nervous system dysfunction. I will perform a randomised-controlled trial of intrathecally administrated antitoxin in 270 adult patients, allocating patients to intrath ecal administration or sham procedure in addition to standard intramuscular antitoxin and routine care. Key Goal 2. To develop a simple prediction tool that can be applied clinically to allow early diagnosis and intervention in autonomic nervous system dysfunction. I will quantify heart rate variability in 60 patients with tetanus, correlating sequential readings with the development of autonomic nervous system dysfunction and outcome. Key Goal 3: To create an age/sex-stratified model o f population immunity in Vietnam to ascertain whether current booster programmes are adequate and what proportion of adults lack protection from tetanus. I will measure serum anti-tetanus antibody concentrations using enzyme-linked immunosorbent assay (ELISA) in 4000 serum samples from a recently-established serum bank containing samples from multiple sites in Southern Vietnam.

Amount: £569,168
Funder: The Wellcome Trust
Recipient: University of Oxford

Data sharing platforms to improve treatment outcomes in neglected tropical diseases 06 Jul 2017

We will develop data-sharing platforms to assimilate and collaboratively interrogate global data on i) schistosomiasis ii) soil transmitted helminths, iii) visceral leishmaniasis, iv) melioidosis and v) scrub typhus. This proposal will support the development of the technical platform and curation of data from tens of thousands of patients enrolled to treatment trials and programmatic data of these diseases for use in collaborative meta-analysis to answer key public health questions. The platform’s technical infrastructure will include secure data upload, auditable mapping of multi-disciplinary datasets to a standardised data structure, searchable data inventory and systems to request and receive data. The governance framework will ensure terms of data access that follow principles of equitable and ethical data sharing under the guidance of Science Advisory Committees nominated by the relevant disease communities. Support for the coordination and production of scientific output from the platform will be provided to ensure impact. Platform construction will leverage the expertise and investment in our existing malaria data platform, the WorldWide Antimalarial Resistance Network (WWARN). Prior funding has supported the development of successful pilot platforms for visceral leishmaniasis and schistosomiasis/soil-transmitted helminths, and we will assess the feasibility and impact of establishing platforms for melioidosis and scrub typhus.

Amount: £1,406,744
Funder: The Wellcome Trust
Recipient: University of Oxford

Future of Animal-sourced Foods (FOAF) 06 Oct 2016

Changes in the amount and type of animal-sourced food (ASF) we consume, and in the way they are produced, are critical drivers of global human health and environmental quality. The project will develop novel policy tools and interventions to allow more informed and effective action to be taken to maximise the health and environmental co-benefits of changes in ASF consumption. We shall build a quantitative food system model incorporating economic, health and environmental modules that will allow the effects of existing drivers and novel policy interventions to be assessed. We shall exploit unique epidemiological resources to provide new evidence about how different types of ASF affect health, and conduct experiments to develop new interventions to influence the consumption of ASFs and ASF substitutes. A social-science component will research how social norms and political economic factors affect the practicality and acceptability of interventions, and how this may be changed. The effects of different types of ASF production on climate change, water use and quality, and ecosystem functions will be measured and brought together for the first time. The project will develop a distinct work stream in China and engagement with multiple audiences will be integral to all its activities.

Amount: £4,391,572
Funder: The Wellcome Trust
Recipient: University of Oxford

Future of Animal-sourced Foods (FOAF) 06 Oct 2016

Changes in the amount and type of animal-sourced food (ASF) we consume, and in the way they are produced, are critical drivers of global human health and environmental quality. The project will develop novel policy tools and interventions to allow more informed and effective action to be taken to maximise the health and environmental co-benefits of changes in ASF consumption. We shall build a quantitative food system model incorporating economic, health and environmental modules that will allow the effects of existing drivers and novel policy interventions to be assessed. We shall exploit unique epidemiological resources to provide new evidence about how different types of ASF affect health, and conduct experiments to develop new interventions to influence the consumption of ASFs and ASF substitutes. A social-science component will research how social norms and political economic factors affect the practicality and acceptability of interventions, and how this may be changed. The effects of different types of ASF production on climate change, water use and quality, and ecosystem functions will be measured and brought together for the first time. The project will develop a distinct work stream in China and engagement with multiple audiences will be integral to all its activities.

Amount: £947,700
Funder: The Wellcome Trust
Recipient: University of Oxford