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Paul Hamlyn Foundation
The Wellcome Trust
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University of Warwick
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Results

Cellular Dynamics and Regulatory Networks Controlling Endometrial Remodelling during the Window of Implantation 17 Jul 2018

The endometrium undergoes iterative cycles of menstrual shedding, regeneration, rapid growth, and differentiation in response to ovarian hormones. During the mid-luteal phase, the endometrium becomes transiently receptive to implantation, heralding the start of a process of intense tissue remodelling, characterized by secretory transformation of glandular epithelium, angiogenesis, differentiation of stromal cells into secretory decidual cells, and activation of specialized immune cells. Several reproductive disorders, including recurrent pregnancy loss, are linked to defects in tissue remodelling at implantation. However, the cellular complexity and dynamic nature of the endometrium have so far precluded precise characterization of the underlying pathological mechanisms and drivers. We will employ high-throughput single-nucleus sequencing to map the dynamic changes in gene expression and chromatin accessibility (cis-regulatory regions) in all endometrial cell types across the luteal phase in defined patient groups. The data will be back-mapped to a future successful pregnancy or miscarriage. This analysis will yield unparalleled insight into the sequence of endometrial events (i.e. changes in cell populations, cellular states, gene expression and transcriptional regulation) leading to a successful or failed pregnancy. Further, 3D organoid cultures, consisting of glands and stroma, will be used to investigate putative drivers of endometrial dysfunction and to evaluate new treatment targets.

Amount: £1,281,629
Funder: The Wellcome Trust
Recipient: University of Warwick

Structure and mechanism of a key bacterial cell division protein 06 Sep 2018

To divide and multiply, bacteria must remodel their cell envelope to facilitate physical separation of daughter cells. FtsEX is a key player in coordinating cell division events on either side of the bacterial inner membrane. FtsEX belongs to the same protein superfamily as the MacB efflux pump and the LolCDE lipoprotein trafficking complex, collectively termed Type VII ABC transporters. Current models for FtsEX activity suggest long range conformational changes in FtsEX regulate periplasmic enzymes responsible for peptidoglycan hydrolysis while maintaining cytoplasmic interaction with the septal Z-ring. Structural and functional data are essential to understand how FtsEX works and to assess viability of inhibition using chemical compounds. This project seeks to characterise the interaction of FtsEX with its binding partners, the role of ATP binding and hydrolysis, and to obtain structural data using X-ray crystallography. The project builds on published work on Type VII ABC transporters and is supported by preliminary data showing FtsEX has been crystallised. The Seed Award will presage future applications to the Wellcome Trust, MRC or Leverhulme Trust to further explore the structure and function of bacterial cell division proteins as targets for future antibiotic development.

Amount: £98,945
Funder: The Wellcome Trust
Recipient: University of Warwick

Connexin 32 evolution to a CO2 sensor 31 May 2018

Connexin26 (Cx26) is the CO2 chemosensor from reptiles to humans. The CO2 sensitivity of Cx26 arose early in the evolution of air breathing and is present in the ancient lungfish ancestor of all tetrapods. However, Cx26 of modern ray-finned fish has lost the CO2-binding motif. In mammals, Cx32 has a CO2 binding motif almost identical to that of Cx26 and is also sensitive to CO2. Strikingly the CO2 binding motif is retained in Cx32 of ray-finned fish. I would like to test the hypothesis that Cx26 and Cx32 have evolved from a common ancestor. An important step in testing this hypothesis is to see whether Cx32 of different ray-finned fish species is sensitive to CO2 and compare the protein sequence similarity. I will transfect fish Cx32 cDNA into HeLa cells and use a simple dye loading assay to test their CO2-sensitivity. I will also quantify the CO2 sensitivity of human Cx32 to give a direct comparison between fish and human Cx32. I will conduct a bioinformatic analysis of Cx32, paying particular attention to the CO2-binding motif, from several fish, amphibian, reptilian and mammalian species. My work will shed new light on the origins of CO2 binding in the connexin family.

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

Diabetic Vascular Disease (DVD): Enhancing our understanding of the cause of DVD 31 May 2018

The two main forms of diabetes are type I and type II diabetes; type I is an autoimmune disease where the insulin producing beta cells are destroyed by the body’s own immune system, and as a result the body cannot produce insulin. Type II, the most common form of the disease accounts for 90-95% of all diabetes. Both types lead to hyperglycaemia and insulin resistance. These causes overproduction of reactive oxygen species (ROS) and via endothelial dysfunction and inflammation, this accumulation of ROS plays a major role in precipitating diabetes vascular diseases (DVD) in these patients. If DVD is not treated the blood vessels will continue to narrow and will eventually become occluded by the deposits of fat. This will lead to ischaemia in the organ which can be fatal if this occurs in the brain or heart. Our overall aim is to better understand DVD at a molecular level and how it is actually caused, and this will be achieved by studying endothelial cells and exposing them to DVD inducing factors and see how they change.

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

Probing the chromatin assembly pathway 18 Oct 2017

Histone deposition to form nucleosomes is an important process underlying all genomic transactions. Research over the last 20 years has put forward the idea of a dedicated histone chaperoning pathway in which histones are transferred between a number of distinct chaperoning complexes that guide their thermodynamic assembly into nucleosomes. This has been difficult to test directly with the currently available toolset for pulse labeling of proteins. Furthermore, mixing of soluble nuclear proteins with cytosolic extracts upon cellular fractionation has complicated defining the nucleo-cytoplasmic division within the pathway, at least through biochemical means. I have recently developed a new approach for pulse-chase labeling of nuclear proteins using a cytosolic tether-and-release strategy that offers some advantages in studying the early stages of the histone chaperoning pathway, which I plan to capitalize on. I also aim to understand in greater detail at the molecular level the interplay between two chaperoning proteins that have been shown to be important in H3-H4 heterodimer formation. My key goals are to (1) investigate the early stages of histone processing, (2) investigate the molecular basis of interaction between sNASP and the H3-H4-ASF1 complex and (3) further develop tether-and-release approaches to investigate fast kinetics of nuclear proteins.

Amount: £921,866
Funder: The Wellcome Trust
Recipient: University of Warwick

Shedding light on platinum chemotherapy: a new mechanistic approach 08 Nov 2017

Despite their widespread clinical use in cancer treatment, platinum(II) complexes, including cisplatin, present critical issues such as severe side effects and onset of resistance. Furthermore, their mechanism of action is not fully understood and no reliable patient stratification tool exists. Novel prodrugs based on photoactivatable platinum(IV) complexes are reduced to cytotoxic platinum(II) species upon irradiation with visible light, providing spatial control of their cytotoxicity. Photoactivated complexes are active in cisplatin-resistant cell lines suggesting a different mechanism of action. I will investigate the mechanism of action of platinum-based anticancer drugs on- and off-target, with focus on photoactivatable complexes and clinically established drugs. The cellular targets will be identified by functional genetics experiments (RNAi/CRISPR-Cas9 screening) and the fate of platinum in vivo will be evaluated by SPECT imaging with platinum-195m labelled complexes in mouse xenograft cancer models (Goal 1). The positron-emitting isotope copper-64 will also be used to evaluate copper-transporter Ctr1 as a biomarker to predict response to platinum-based chemotherapy (Goal 2). Based on these findings, I will modify photoactivatable platinum(IV) complexes (i) to reduce their off-target toxicity by attachment to antibodies targeting specific cancer-cells receptors and (ii) to enhance cytotoxic effect upon photoactivation, by attachment to light-harvesting chromophores (Goal 3).

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

Open Access Award 2017/18 30 Sep 2018

Not available

Amount: £42,025
Funder: The Wellcome Trust
Recipient: University of Warwick
Amount: £4,000
Funder: The Wellcome Trust
Recipient: University of Warwick

Analysing the chromatin and transcriptional landscapes controlling endoderm cell fate decisions during zebrafish embryogenesis 04 Dec 2017

The endoderm germ layer of the vertebrate embryo makes major contributions to the respiratory and gastrointestinal tracts, and all associated organs. The key goals of this project are to exploit the advantages of zebrafish to: 1. Investigate heterogeneity of gene expression amongst endodermal progenitors prior to mature organ formation to define discrete expression patterns controlling development of distinct endodermal tissues in vivo. 2. Characterize dynamic expression patterns controlling emergence of distinct progenitor populations. 3. Identify genomic cis-regulatory modules controlling expression of key lineage-specific genes. 4. Develop multi-purpose fluorescent reporter and Cre-driver transgenic lines to facilitate future detailed study of specific lineages throughout organogenesis. Aims 1 & 2 will be achieved through single-cell RNA-seq characterization of thousands of cells isolated using pan-endodermal Tg(sox17:GFP) transgenic line at multiple timepoints between gastrulation and budding of endodermal organs, followed by detailed bioinformatics analyses. Aim 3 will be achieved through ATAC-seq characterization of chromatin accessibility at identical developmental stages. Aim 4 will be achieved by molecular cloning of putative cis-regulatory modules revealed by ATAC-seq for single-cell RNA-seq candidate genes followed by Tol2 transposon transgenesis. The output will be more detailed understanding of endoderm cell fate regulation and novel transgenic lines to seed future projects and grant applications.

Amount: £99,998
Funder: The Wellcome Trust
Recipient: University of Warwick

Pre-conception genetic screening for conditions of uncertain or variable prognosis: social and ethical implications 05 Apr 2018

Awarded funds are for: - Developing a multi-media art installation from the research findings with the artist, Esther Fox. This installation will include an immersive soundscape capturing the complexities of genetic screening using voiced verbatim text from interviews and an interactive computer game that navigates players through life-like scenarios relevant to genomics. Many disabled people, however, face barriers when participating in cultural life, and a static exhibition does not adequately remove these. Additional funds are therefore requested to increase the inclusivity and accessibility of the installation through the use of touring and production of a film for digital dissemination. Given the centrality of the views of people with disabilities to this research, inclusivity and accessibility are of paramount importance. To achieve this we will: - Collaborate with a digital theatre and media company, STAMP, to create a touring installation. This will be exhibited for 4-5 months in 2019 at approximately five UK Science Festivals and other public venues (e.g. Cheltenham Science Festival, British Science Festival, Think Tank Birmingham). - Film the touring installation and conduct 2-3 minute ‘sound bite’ interviews with attendees. - Post the resulting film on the project website/social media accounts. Also link it to the websites of relevant charities and organisations (e.g. Genetic Alliance UK, condition-specific support groups, GeneWatchUK, US Center for Genetics and Society) - Submit the film to ‘Disorder’, the International Rare Disease Film Festival. - Evaluate the impact and reach of the installation and film through interviews, written and electronic feedback and social metrics.

Amount: £38,100
Funder: The Wellcome Trust
Recipient: University of Warwick

Building the NHS: Planning, Public Opinion and Britain’s New State Hospitals, 1945 – 1974 08 May 2018

My PhD will investigate the planning and design of new state hospitals in the years immediately preceding the NHS and during its early years. Although well recognised as a formative period for the service, there has been little rigorous research into exactly how health policy functioned in practice during this time. Impressions in both public discourse and scholarship have instead been shaped by the rhetoric of high political figures and senior civil servants who have emphasised the benign, technical, and rational aspects of decision-making. This PhD project will argue a new approach is required. Through a series of four hospital-based case studies of planning and design, it will evidence the power of local opposition and support, comparatively illustrate the persistent inequalities in healthcare, and will uncover forgotten discourses on the future of the NHS. It will restore the cultural, local, and discursive processes that really determined the progress and delay of health policy. Moreover, It will explain why both policymakers and historians alike have sub/consciously favored narratives of objectivity over a broader reading of local and regional sources. My ultimate goal in doing so is to evidence how the NHS was really built and its meaning created.

Amount: £95,368
Funder: The Wellcome Trust
Recipient: University of Warwick

Hygiene and our relationship with nature – achieving a better balance? 18 Jun 2018

Physical contact with dirt in the natural world poses a risk of infection. But does our concern to be hygienic limit our familiarity with, and therefore our respect for, the outdoor environment? Do we as a result persist with practices that threaten both our health and that of the planet? Working with Warwickshire Wildlife Trust (WkWT), based at their Brandon Nature Reserve, I will investigate how concerns about hygiene affect interaction between humans and the natural world. I will evaluate practices in this regard at Brandon, to establish how far this location can be held up as a model in terms of the ways institutions safeguard members of the public whilst having minimal impact on the environment. I will interview WkWT’s partner organizations such as schools, and report on how they minimize risks whilst promoting respect for nature. I will talk to staff and visitors at WkWT about balancing hygiene with a love of nature. Building on these conversations, I will formulate a questionnaire with which to approach the wider public. Working with WkWT’s schools team, I will devise a range of curriculum- linked workshops exploring how animals keep clean in the wild in comparison with human practice.

Amount: £12,149
Funder: The Wellcome Trust
Recipient: University of Warwick

Puffery or Policy: E-cigarettes and the role of the media in the implementation of medical and public health advice 18 Jun 2018

My project focuses on the e-cigarette industry to explore the role of the media on public opinion. Both print press and audio-visual media strongly influence the socio-cultural values attached to addictive substances. They portray the relationship between the supplying industries and public health; frame both promotional advertising and health warnings; and finally, provide the multiple-platforms of information (and addiction) transmission. The public can be overwhelmed by this wealth and profusion of contradictory claims, undermining genuine expert recommendations. Research can help to overcome this. A chronological evaluation of textual and audio-visual media, tracing the shifting relationship and negotiations between the many stakeholders (public health, Cancer Research UK, the media, e-cigarette industry and consumers), will demonstrate the changing socio-cultural associations of e-cigarettes. Having established this background, interviews with these stakeholders will explore the advertising and health recommendations of both health policy and the e-cigarette industry across different media platforms -- exploring which advice is trusted and followed. This project creates a transferable framework and approach to build positive relationships with emerging industries promoting new products not easily categorised as ‘healthy’ or ‘unhealthy’. This research also assesses the most effective and appropriate media platforms to broadcast health advice in the future.

Amount: £7,625
Funder: The Wellcome Trust
Recipient: University of Warwick

Alchemy, Medicine, and Pharmacology in Medieval Islam: Rāzī's Twelve Books 23 Jul 2018

Razi (d. ca.925) was one of the greatest physicians of the classical Islamic world and one of its greatest alchemists. His encyclopaedic introduction to alchemy, The Twelve Books, had an enduring influence on medicine and pharmacology, but the book itself fell out of favour on account of Razi’s reputation as an heretical freethinker. Thus, The Twelve Books has long been presumed lost and its impact underestimated. Through recent advances in manuscript cataloguing, however, its chapters can now be located dispersed through archives across the globe. Previous studies have explored the links that have existed between medical and alchemical traditions since the latter’s origin in Greco-Roman antiquity and have suggested ways that mediaeval Islamic alchemist-physicians may have made alchemical contributions to medicine. Nonetheless, clear proof that medicine benefitted directly from Greco-Arabic alchemy has remained elusive. It has even been doubted whether Razi's own alchemical and medical thinking were integrated. By re-assembling and editing the fragments of The Twelve Books for the first time, this project will prove that they were. An English translation and detailed commentary will demonstrate of the contribution of Greco-Arabic alchemy to the development of medicine in both the Islamic world and Europe.

Amount: £190,519
Funder: The Wellcome Trust
Recipient: University of Warwick

What’s at stake in the fake? Indian pharmaceuticals, African markets and global health 30 Jul 2018

For the past several decades, global health researchers and policy-makers have raised the alarm about the growing threat that fake pharmaceuticals pose to global health. Often these concerns are framed in terms of particular places and people, for example, fake drugs from India imperil Africans’ health. We subjected these high-profile and oft-repeated claims to scrutiny. This exercise produced some unexpected findings. Across scientific, policy and popular literature, we found substantial misalignments between (1) the strength of claims about fakes alongside (2) the relative weakness of these claims’ evidence. Scientific literature in particular raised questions about apparent certainties, such as: What, exactly, are fake drugs? Are fake drugs necessarily dangerous? Where do they come from? When the global supply of life-saving medicines is beset by worries about safety, governments and citizens face difficult decisions about how to allocate scarce resources. By asking questions about these worries, we hypothesize that the problem of fake drugs is not solely a pharmacological problem; it is also a social problem. Two questions guide our project’s historical and ethnographic research What accounts for the rise of fake-talk—the wide-spread and urgently-reiterated set of concerns about the dangers that fake drugs present? What are the effects of fake-talk?

Amount: £755,691
Funder: The Wellcome Trust
Recipient: University of Warwick

Streamlining Galen: Medical Summaries and the Transmission of Medicine in Medieval Islam 30 Jul 2018

We propose to study medical teaching and practice and the changing face of Galenic medicine in Islam through the medium of a prolific but largely unstudied genre of writings, Arabic summaries of Galen. A fundamental re-evaluation of these sources will show how they served as primary learning tools for medical students and doctors, a means of demonstrating medical credentials, and as instruments for the reconfiguration of the ancient medical heritage. In addition to a comprehensive survey of Arabic Galenic summaries, we will compile and digitise a select corpus of such texts, and analyse and compare them with the Galen treatises in Arabic translation that formed the basis of the summaries, using digital tools and techniques of close reading. The proposed outcomes include (1) a study of the history, nature and purposes of summaries in Arabic medical literature; (2) monograph studies, editions and translations of a number of these works; (3) articles on individual authors of summaries and their working methods; (4) the proceedings of a conference on the role of auxiliary texts in the evolution of Galenic medicine in antiquity and the Middle Ages; and (5) a publicly available digital corpus of summaries and related texts.

Amount: £812,206
Funder: The Wellcome Trust
Recipient: University of Warwick

'The Royal Albert’: Childhood Idiocy and the Institutionalisation of Children’s Care in Victorian and Edwardian Britain. 08 May 2018

This PhD will investigate the social and medical history of children’s care in Victorian and Edwardian Britain, using the Royal Albert Institution as a case study. By the turn of the nineteenth-century, this establishment was one of the largest institutions in the UK devoted to the care and treatment of children deemed ‘idiots’ and ‘imbeciles’. The PhD intends to document the evolution of the Royal Albert from its inception in 1864 to 1913, providing a broad chronological overview of its development and contribution to wider debates about childhood and disability in the late nineteenth and early twentieth centuries. Historical studies of childhood have undergone something of a renaissance in the late twentieth-century, forging new understandings of the ways in which childhood as a social condition and temporal state were shaped in different contexts. The PhD intends to extend these exciting developments and provide an innovative contribution to contemporary advancements in disability studies which seek to 'dislocate' conventional views of the disabled and the marginalised. It will develop our understanding of how children with disabilities and mental disorders intersected with emerging healthcare systems, and refine our view of the interplay between the state, families and medical professionals in managing their care.

Amount: £93,027
Funder: The Wellcome Trust
Recipient: University of Warwick

Safeguarding people with mental heath issues or learning disabilities during contact with the police 06 Nov 2017

People with mental health issues account for approximately 20-40% of police time and a substantial proportion of deaths in police custody. However, police forces are still struggling to identify interventions to better safeguard the welfare and lives of the mentally vulnerable. Using four Wellcome Library archives as a starting point, this project will develop a much needed evidence-base for understanding (i) how these health issues have come to dominate police time, (ii) what barriers exist for better police-health partnerships and, (iii) how to overcome them. The literature is patchy and highly dispersed, with even less research on safeguarding people with the closely related issue of learning disabilities. This project will take place at a time when national government, police forces and local health trusts are keen to develop more integrated services but face considerable barriers to making them successful. Therefore, this project is timely and will enhance our understanding about why progress is frustrating slow, improve decision-making, and identify conceptual black-holes for future inquiry. Recommendations will be developed and some will be tested for a subsequent, major grant application to the Wellcome Trust in collaboration with at least two police forces and their health trusts.

Amount: £18,849
Funder: The Wellcome Trust
Recipient: University of Warwick

MA in the History of Medicine 11 Jul 2018

The MA in the History of Medicine aims to introduce students to the advanced study of the history of medicine, and to equip them with the conceptual and practical skills to carry out independent historical research in this field. The students on the MA are encouraged to engage with a range of concepts, and to place developments within medical theory and practice in a broad social and cultural framework. The Term One core module ‘Themes and Methods in Medical History’ is designed to introduce students to some of the main historiographical approaches and debates within the history of medicine from the early modern period to the twenty-first century. The Term Two core module, 'Matters of Life and Death', addresses three sets of topics in the history of medicine (broadly construed) selected by its students from a menu of possible options. Possible topics range across the expertise of teaching and research staff in the Centre for the History of Medicine, and of our Associates in the wider University context. Students actively engage with a wide range of sources available to the historian of medicine (e.g. medical texts, practice records, diaries, case records, public health reports and health propaganda, and visual sources).

Amount: £83,671
Funder: The Wellcome Trust
Recipient: University of Warwick

‘People like you’: contemporary figures of personalisation 01 Feb 2017

We aim to contribute to critical medical humanities by investigating an emergent culture of personalisation in the UK, associated concepts of the person and health. We expect to stimulate debate on personalised medicine by showing how it can be understood more fully in relation to other personalising practices and how features shared across this broad field are consequential for our wellbeing. Our innovative figural approach will be applied to case studies of both top-down and open-ended practices of personalisation in medicine, data science and digital culture. In collaboration with creative consultants, we will conduct practice-led research to produce additional insight into the role of participation in, and the sense made of, personalisation. Our aim is to put the ‘person’ back into personalisation, and relate such persons to the data collected from them and on their behalf. This approach will allow us to investigate individuals’ sense of self, agency and identification with others. It will allow us to consider the implications of new techniques for stratifying ‘persons’ precisely in shaping health outcomes and healthcare priorities. In sum, we will assess whether personalising practices, considered together, are influencing taken-for-granted concepts of the person with consequences for individual and collective health.

Amount: £368,906
Funder: The Wellcome Trust
Recipient: University of Warwick