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Determining the role of activity-dependent bulk endocytosis via new molecules 30 Nov 2016

Synaptic vesicle (SV) endocytosis is essential for the maintenance of neurotransmission, particularly during intense neuronal activity. Under these conditions the dominant endocytosis mode is activity-dependent bulk endocytosis (ADBE), suggesting it should perform a central role. However determining the physiological role of ADBE has been hindered by a limited understanding of its molecular mechanism. We propose to address these challenges by discovering presynaptic molecules with a specific and selective role in ADBE. This will be achieved by integrating functional proteomics, a spectrum of complementary SV recycling assays and detailed molecular studies to establish a mechanistic basis for key steps in ADBE. This will facilitate generation of transgenic rodents and molecular tools to disrupt / enhance specific stages of ADBE in vivo. Importantly, this research strategy is already established with a series of presynaptic molecules discovered that have specific roles in ADBE. We will exploit these findings to determine how ADBE impacts on neurotransmission at the synaptic, neuronal, circuit and behavioural level. This work will reveal fundamental mechanisms that underpin neurotransmitter release during high intensity firing, and potentially ADBE-specific interventions that will manipulate presynaptic performance exclusively during intense neuronal activity.

Amount: £1,783,875
Funder: The Wellcome Trust
Recipient: University of Edinburgh

Global dynamics of mRNA accumulation and translation in embryonic development 30 Nov 2016

The ability of cells to generate complex gene expression patterns is fundamental to multicellular life. While global mRNA levels can now be routinely determined using ‘omics technologies, a major gap in our knowledge is how a cell produces these mRNA levels with the correct temporal dynamics. In addition, the fate of individual mRNAs represents another variable that is rarely globally considered. Therefore, the overarching question addressed in this proposal is: How are global mRNA accumulation dynamics and translatability harmonised with developmental timing to control cell fate decisions? We will exploit the rapid development and tractability of Drosophila to address this question in a developing embryo. We will model the dynamics of mRNA synthesis, processing and degradation across early embryogenesis and integrate these data with the export efficiency and translatability of mRNAs. For individual mRNAs the dynamics will be validated in vivo using live imaging and modeled to give single cell spatiotemporal resolution. For key developmental genes we will perturb mRNA production rates and translatability to determine the effect on protein function and the accuracy and robustness of dorsal-ventral patterning. Overall our data will reveal how dynamic regulation at every step in the gene expression pathway drives developmental patterning.

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

Unravelling the CTLA-4 immune checkpoint: from cell biology to clinical application. 30 Nov 2016

The CTLA-4 pathway is a key immune regulator whose absence or mutation leads to profound autoimmunity. CTLA-4 and its relative CD28 have opposing inhibitory and stimulatory functions respectively and interact with two ligands CD80 and CD86. Despite the key role of this pathway in immune regulation and high profile therapies in tumour immunology, our understanding of how CTLA-4 functionally interacts with its two natural ligands is remarkably incomplete. The aim of this proposal is to generate a robust molecular, cellular and functional framework for CTLA-4 biology which can be used to understand the impact of disease mutations, which are being identified as a result of next generation sequencing programmes, and generate knowledge which can underpin new approaches to manipulation of this key immune axis. We will address three key aims: 1). What is the cellular machinery used by CTLA-4 to capture and transfer ligands between cells? 2). How do CTLA-4 interactions with its natural ligands influence its function? 3). How do clinically identified mutations inform our understanding of the CTLA-4 pathway?

Amount: £1,653,759
Funder: The Wellcome Trust
Recipient: University College London

A systems approach for understanding cell surface dynamics in trypanosomes 30 Nov 2016

The surface membrane and endosomal system of protozoan pathogens directly interfaces with the host; mediated functions including immune evasion, environmental motoring and drug interactions. Recently it has emerged that surface composition and the mechanisms controlling membrane protein turnover in trypanosomatids are highly divergent, and that these processes also are connected with drug interactions. We have clear evidence for complex control based around ubiquitylation, but the roles of many surface proteins remain cryptic. I propose a program of work to integrate, in a system wide manner, how these novel aspects of biology converge to maintain the parasite surface. 1. Examine the mechanisms of ISG and AQP turnover,2. Evaluate the potential of ISGs for novel anti-trypanosome drug delivery,3. Assess the essentiality of ISG protein families in vitro and in vivo using genome editing.4. Refine our understanding of the clathrin and ESCRT sorting systems of trypanosomes to determine how these processes mediate the transport of ISGs, AQPs and the surface proteome in general. Each of these aspects will exploit a combination of state of the art proteomics, super-resolution microscopy and novel genetic tools to understand in greater detail the importance of surface proteins to trypanosome biology, virulence and infectivity.

Amount: £1,393,659
Funder: The Wellcome Trust
Recipient: University of Dundee

Health and economic benefits of water-sensitive revitalisation in informal urban settlements 06 Oct 2016

Urbanisation is a major demographic trend globally. Informal settlements account for much urban growth, exacerbating the inextricably linked challenges of sanitation, water provision, and public health. The conventional ‘big pipes’ solution to these challenges has changed little in 150 years, comes at major financial, environmental, and social costs, and frequently overlooks informal settlements. We have pioneered an alternative, water-sensitive approach that integrates sustainable design with the management of the water-cycle, benefiting human health and urban ecosystems. This decentralised, climate-change sensitive approach provides financial flexibility for multistage developments and adaptability to future technologies. It promises a solution to the water services challenges of informal settlements, yet has only been demonstrated in developed world settings. We will examine whether the water-sensitive approach can be applied to revitalise developing-world informal settlements to improve environmental and public health outcomes. Our evidence-based assessment of its efficacy across 24 settlements, poorly served by water infrastructure in Makassar and Suva, will deliver the first public health and environmental data on the benefits and risks of water-sensitive approaches. Our scientific, economic and implementation findings will provide the basis for profound changes to infrastructure policies, investments, loan strategies, and their sustainability across the Asia-Pacific and the developing world.

Amount: £364,741
Funder: The Wellcome Trust
Recipient: Wellcome Trust Sanger Institute

Complex Urban Systems for Sustainability and Health (CUSSH) 06 Oct 2016

The CUSSH programme will deliver strategically vital global research on the complex systemic connections between urban development and health. Based on transdisciplinary methods, it will develop critical evidence on how to achieve the far-reaching transformation of cities needed to address vital environmental imperatives for population and planetary health in the 21st century. Its core components include: a systematic review of evidence on potential solutions; the development and application of methods for tracking the progress of cities to towards sustainability and health goals; the development and application of models to assess the impact on population health, health inequalities, socio-economic development and environmental parameters of alternative urban development strategies to support policy decisions; iterative in-depth engagements with stakeholders in partner cities in low-, middle- and high-income settings, based on participatory methods, to test and deliver the implementation of the transformative changes needed to meet local and global health and sustainability objectives. Through these steps, the project will provide transferable evidence on how to accelerate actions essential to achieving population-level changes in such areas as energy provision, transport infrastructure, green infrastructure, water and sanitation, and housing. Associated public engagement and training, based on principles of co-generation of research, will be embedded throughout.

Amount: £149,988
Funder: The Wellcome Trust
Recipient: University College London

The Edinburgh Clinical Academic Track (ECAT)-Plus Programme 30 Nov 2016

ECAT-Plus aims to extend the successful ECAT (Edinburgh Clinical Academic Track) Wellcome Trust Clinical PhD programme in Edinburgh and to increase trainee numbers from 5 to 7 annually. The key aims of this application are to increase diversity, maintain momentum and increase capacity in clinical academic training. Our key goals are to: 1. Develop a programme to encourage and support increased diversity and inclusion in the academic workforce, addressing recruitment into academic training but also achieving equivalent retention and achievement, especially with regard to gender. 2. Address the challenge of maintaining research momentum post-PhD through targeted support. We have identified the postdoctoral period and return to clinical training as requiring focus on mentorship and on award of targeted research money distributed through a Research Maintenance Fund. 3. Increase capacity in veterinary training to accommodate high demand from excellent candidates, continuing to recruit vets and medics using the same criteria and training them within a single academic cohort. 4. Increase overall capacity of the scheme by 2 trainees annually to compensate for loss of response-mode Wellcome Fellowships and to achieve cohort sizes appropriate for a diverse workforce with variable speeds of career progression.

Amount: £6,399,500
Funder: The Wellcome Trust
Recipient: University of Edinburgh

A Public Engagement package to support research towards reductions of antimicrobial usage in farming systems in the Mekong Delta of Vietnam (Intermediate Clinical Fellowship Grant No. 110085/Z/15/Z). 27 Dec 2016

The ViParc project (Vietnamese Platform for Antimicrobial Reductions in Chicken Production) started in March 2016. Relevant research staff (project coordinator and laboratory coordinator, both based in OUCRU) have been recruited. Permissions from the Provincial People’s Committee and Sub-Department of Animal Health in the Mekong Delta province of Dong Thap (SDAH-DT) have been granted. A detailed budget has been drafted and agreed with SDAH-DT. A planning meeting was successfully held on 22nd June 2016 in Ho Chi Minh City with participation of all project partners (including the Royal Veterinary College, Institute of Poultry Diseases and University of Can Tho). A visit to SDAH-DT was carried out to identify potential project veterinarians and to provide them with training on post mortem techniques for poultry (led by Prof. Hafez). Laboratory equipment to carry out testing of antibiotic residues in meat has been purchased and installed in OUCRU, and training has been provided to the laboratory coordinator. A website has been launched to inform about ViParc project activities ( This has a designated Public Engagement section. A number of field equipment items have been purchased and delivered to SDAH-DT. All forms and SOPs have been developed, as well as a database to capture both laboratory and field data. A meeting with SDAH-DT to discuss setting up the CABs is arranged for mid-September.

Amount: £75,979
Funder: The Wellcome Trust
Recipient: University of Oxford

Cremation Archive Cataloguing Project 25 Nov 2016

The principal objective of this project is to catalogue and make accessible for research archive material of the Cremation Society of Great Britain. This will provide an invaluable resource for academic research by various disciplines into cremation and society's disposal of its dead. The Cremation Society of Great Britain first deposited journals and part of its archive with Durham University in 1998. These were catalogued and made available for research. The Society then made a further substantial addition to that material in 2015, which now needs to be catalogued. The material covers all aspects of the Society's administration dating back to the late 19th century, the provision of its facilities for members, including funding schemes, and the development of the crematoria themselves. It also includes records of the International Cremation Society, particularly their annual conferences around the world. A professionally qualified archivist will be employed for six months to: 1. Sort and produce an online catalogue of the archival material to the current best practice ISAD(G) guidelines, overseen by similarly qualified professionals. 2. Package, box and label the material using the appropriate archival-quality materials to ensure long-term preservation and accessibility of the material, with the advice of professionally-qualified conservation staff.

Amount: £21,416
Funder: The Wellcome Trust
Recipient: University of Durham

The Peckham Experiment: Fiction from the Archives 15 Nov 2016

Over the course of 5 months, I propose to research the archive of the Pioneer Health Centre, held at the Wellcome Library, and write a series of prose poems, fictions and creative-critical texts based on the materials in the archive. The project builds on my existing research and writing around this archive, allowing me to realistically propose several substantial goals within a relatively compressed timeframe. I aim to: Produce a significant body of prose texts to be published in part in literary journals and as a collection by a respected press in the emerging genre of experimental or hybrid creative-critical prose. Explore through these texts ideas from the archive with contemporary relevance, such as the relationship between the individual and the collective, or between self-organisation and experimentation. Advance the practice of creative-critical writing and further the argument that creative writing can produce new insights into a topic. Develop a new audience for archival writing, the Peckham Experiment archives and the Wellcome Library’s collections via my publications, discussions with peers and a day-long public engagement workshop.

Amount: £25,000
Funder: The Wellcome Trust
Recipient: No Organisation

Creativity and Equity in STEM Learning. 07 Nov 2016

The University of Washington and Science Gallery Dublin, in partnership with several US and UK organizations, propose a Science Learning+ Phase 2 project: Creativity and Equity in STEM Learning. The project aims to drive and transform a next generation of broadening participation efforts targeting teen-aged youth from communities historically underrepresented in STEM fields (hereinafter "under-represented youth"). The project investigates how out-of-school time (OST) programs, integrating epistemic practices of both the arts and sciences, in the context of consequential activities (such as creating radio segments, museum exhibitions, or online games for the general public), can more broadly appeal to and engage youth who do not already identify as STEM learners. This project builds on a Wellcome Trust SL+ Phase 1 award (105948/Z/14/Z).

Amount: £649,478
Funder: The Wellcome Trust
Recipient: Trinity College Dublin

‘Biofuels’ and respiratory health – the potentials of the archaeological record 10 Nov 2016

In the light of climate change and the negative environmental consequences of burning fossil-fuels, an increasing focus has been on ‘biofuels’ as sustainable alternatives. However, the use of silica-rich renewables can have detrimental effects on urban air quality and respiratory health. We will explore this tension by applying modern air quality modelling to a long-lived archaeological settlement, where previous research shows a significant shift in fuels over 1000 years, alongside decreasing settlement density. We will address two problems. The first is our understanding of the long term (> lifetime) relationship between ‘biofuel’ burning, settlement density, and respiratory health. The second is the public understanding of the detrimental effects of these fuels, which are, perhaps erroneously, considered ‘cleaner’ than fossil-fuels. There is great potential to explore the role of archaeology, in understanding this relationship over the long-durée, and as a tool for communicating health issues to communities at risk. The nature of the archaeological record enables a long-term perspective which can inform circumstances of use with minimal health risk. The key goals are to establish a network of interdisciplinary collaborators from archaeology, civil engineering and modern environmental health research, and conduct feasibility studies to support an application for a larger award.

Amount: £42,621
Funder: The Wellcome Trust
Recipient: Newcastle University

Socialist Medicine: an Alternative Global Health History 10 Nov 2016

The aim of this Seed Award is to develop an Investigator Award application for a project on the role of socialism as concept, and socialist internationalism as practice in shaping global health history, focusing primarily on the Cold War era. The project to be developed with the help of this grant will investigate socialism and socialist internationalism simultaneously from within and from without. First, it will track how ideas of public health and medicine circulated among socialist countries and welfare states, which practices and concepts were adopted as opposed to others, and how local solutions fed back to the overall idea of health in national and international contexts. Second, it will explore how socialist medicine engaged with Western and non-aligned health systems and global health programs. The project in this sense provides a significantly new perspective on histories of global health. Key goals: develop an Investigator Award application conduct archival scoping on four continents identify research questions, concepts and methods through workshops build local research capacity and create network of research assistants, experts and scholars in key research sites develop an academic network in which the project can be embedded establish Advisory Board for research project

Amount: £47,082
Funder: The Wellcome Trust
Recipient: University of Exeter

Therapeutic Commodities: Trade, Transmission and the Material Culture of Global Medicine 10 Nov 2016

Therapeutic commodities – goods considered valuable for the improvement of health – have local as well as global histories. This project aims to understand the history of therapeutic commodities by using a material culture approach, meaning a focus on socio-cultural contexts in which humans assign meanings to commodities, as well as analysis of their materiality: the qualities and meanings assigned to substances, the ways in which substances came into being, including technologies that created, developed and produced the commodity. I propose to view these two as mutually constitutive aspects of a material approach to medicine. Studies of trade and the transmission of medical knowledge tend to reduce therapeutic commodities either to unchanging goods that move in line with supply and demand, or to characteristic features representing separate systems of knowledge. Instead, this project seeks to bring together scholars who work on therapeutic commodities across time (from the early modern to the contemporary) and space (Eurasia, South Asia, Africa and the Americas), and in different academic environments, to challenge existing narratives about the circulation of therapeutic commodities. The ultimate aim is to write a new history of therapeutic commodities, mapping their global socio-political and cultural lives across time and space.

Amount: £47,264
Funder: The Wellcome Trust
Recipient: University of Warwick

What's at stake in the fake? A contemporary cultural history of fake drugs and India 10 Nov 2016

Preliminary investigations suggest the global anti-counterfeiting movement's regular claims about India's role as a major producer of fake drugs are poorly aligned with observable evidence. If accurate, these findings suggest that practical measures to strengthen access to safe medicines--for the world’s rich and poor--need substantial, and urgent, rethinking. In order to test inital findings, this award will support further research into the nature of India's pharma sector since c1970 (size, expertise, domestic and export markets), with particular attention to the role of India as the global south's generic drugs manufacturer. In particular, materials will be gathered from official and unofficial published archives (in India and elsewhere) as well as from interviews in India with those who write policy, those tasked with implementing policy, drugs manufacturers, pharmacists, prescribing physicians and medical representatives. Global health scholars have already noted India's generics within anti-counterfeiting activities. India's reputation as a fakes manufacturer, however, has gone largely unquestioned. Findings will be aired at the National Bioethics Conference (India) as well as at a bespoke international medical humanities workshop. These presentations will form the basis of published outputs as well as an Investigator Award application to be submitted to the Trust in July 2017.

Amount: £35,523
Funder: The Wellcome Trust
Recipient: University of Warwick

Augmenting the Body: Disability, Care and the Posthuman 10 Nov 2016

Body augmentation takes many forms, whether personal adaptation or the rehabilitation of those with disabilities, and ranges across the physical, cognitive, philosophical and technological. It also questions the constitution of norms and the status and viability of the body when considered in terms of its presence, boundaries and activities. Our aim is to develop a cross-disciplinary research approach to ideas of augmentation, noting how they reflect and are influenced by cultural narratives that drive contemporary obsessions with robots and a posthuman space ‘beyond’ conventional apprehensions of the body and selfhood. We will use a broad understanding of augmentation, including ideas of care and psychological wellbeing as well questions relating to technology and the cyborg/biohybrid body, and will focus on both physical and cognitive augmentation in exploring the interaction of the human and non-human. We will concentrate on disability because it raises central questions about difference, challenges assumptions about norms, and works both as a material concept located in the world of patients and rehabilitation, and a set of metaphors that reflect current thinking of what it means to be human. Ultimately, through co-produced research, our project seeks to change the ways in which disability experience is represented and understood.

Amount: £28,922
Funder: The Wellcome Trust
Recipient: University of Leeds

Sex-dependent gene regulation in immune cells 29 Nov 2016

Sex is a fundamental but frequently overlooked biological characteristic of humans and model organisms that affects immune responses. I aim to develop integrative bioinformatics approaches to interrogate publicly available transcriptomics and epigenomics datasets to delineate the sex-determined molecular mechanisms that modulate the immune system. My group will generate models of the sex- and cell-specific gene regulatory networks for the major blood cell types where data is available. We will study how these sex-specific networks derived from healthy cells are influenced by infections and other disease conditions. We will develop new bioinformatics tools to integrate the sex-specific transcriptional programs with diverse sources of epigenomics information to identify the distinct chromatin configurations that underlie the different immune responses in men and women. These results will provide the necessary framework to understand the molecular differences in men and women in response to infections, autoimmune disease and in immunodeficiencies. This will provide new insights underlying disease pathogenesis and facilitate personalized therapy for men and women.

Amount: £78,166
Funder: The Wellcome Trust
Recipient: Newcastle University

How does airway macrophage glycolytic reprogramming contribute to fibrotic lung disease? 29 Nov 2016

Idiopathic pulmonary fibrosis (IPF) is the most common form of interstitial lung disease and is associated with high mortality. IPF therapies are limited and there is a significant need to understand the mechanisms involved. Airway macrophages (AMs) are the most abundant immune-cell in the IPF lung. Recent work demonstrated that IPF-AMs are characterised by high expession of glucose transport molecules; however, whether AM-glycolytic programming contributes to the pathogenesis of lung fibrosis remains unknown. My preliminary data indicates that IPF-AMs have a unique metabolic phenotype, characterised by reduced succinate and elevated Irg1 expression, a negative regulator of the citric acid cycle via itaconic acid. I hypothesise that AM glycolytic reprogramming contributes to the pathogenesis of lung fibrosis and manipulation of AM metabolism via itaconic acid, can ameliorate the disease. First, I will determine AM metabolic signatures in the fibrotic lung by metabolic assays in IPF-AMs and murine models. Second, I will assess Irg1 and itaconic acid levels in patient BAL/lung biopsies. Additionally, I will utilize siRNA knockdown in IPF-AMs and in parallel, Irg1-/- mice. This work will provide proof of principle for development of therapies which correct AM-metabolic dysregulation during IPF, paving the way for future grant applications and clinical studies.

Amount: £96,063
Funder: The Wellcome Trust
Recipient: Imperial College London

The role of autophagy in cancer cell motility 29 Nov 2016

This project will investigate the role of autophagy in cell motility taking advantage of novel prostate cancer cell lines that mimic stages of disease progression (including EMT and metastasis) available through my collaborators at NTU. In particular it will address the role of the actin nucleator JMY, a p53 co-factor that impacts of autophagosome formation, cell motility and survival in autophagy-mediated effects on cell survival and the role of actin nucleation. Specific goals during the duration of the funding: -assess autophagy levels (both basal and induced) in cancer cells lines and correlate with cell motility and invasion (also assessing cell survival and adhesion/motility events, using impedance measurements, to distinguish between effects on proliferation vs motility). -Assess impact of JMY on autophagy-mediated motility (using specific mutants to distinguish autophagosome targeted vs not, and Arp2/3-independent vs dependent actin nucleation. -Assess impact of modulating autophagy levels on cell motility (i.e., through siRNA/CRISPR-Cas9 targetting of JMY and autophagy initiator proteins and small molecule inhibitors of various stages in autophagosome formation).

Amount: £71,786
Funder: The Wellcome Trust
Recipient: Nottingham Trent University