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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

International symposium on poetry and medicine to be held at Warwick University on 10 April 2010 13 Apr 2010

The aim of the symposium is to consider academic approaches to medicine as a historical and current theme in literary poetry, poetry by and for patients and health professionals and in poetry as therapy. Medicine is to be considered in its broadest sense. In particular the Symposium aims to draw together interests in poetry and medicine in the writings of poets, effects of illness on writings of poets, and poetry as therapy for patients and interest as well as a training tool for health professionals. Awards for the new annual International Hippocrates Prize for Poetry and Medicine will be announced during the Symposium. This new Award attracted over 1600 entries from 28 countries from health professionals, patients and members of the public.

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

Epidemics in Context: Hippocrates, Galen, and Hunayn between East and West to be held at the Warburg Institute on 12-13 November 2010 13 Apr 2010

The conference will build on the current Wellcome project headed by P. E. Pormann and S. Swain to edit and translate into English the medieval Arabic version of Galen's commentary on the Hippocratic Epidemics. A team of international scholars will present papers on aspects of ancient Greek and medieval Islamic medicine in the context of our new work on the first part of Galen's commentary. Epidemics is one of the most important parts of the Hippocratic Corpus and is famous for its inclusion of many case histories. The Greek text is in poor shape and the Arabic of the great translator-physician Hunayn ibn Ishaq is of value to the whole commentary and specifically for those parts lost in Greek (including most of Bk 2 and Bk 6). Our new text and translation of Galen on Epidemics Bks 1 and 2 will be available before the conference as the focus of the discussions. It offers a first-class opportunity for leading scholars to make comparisons between the Arabic-Islamic tradition and its Greek predecessor. The resulting volume will appeal to all those interested in ancient and medieval medicine and the cultural-scientific legacy of antiquity which is shared between East and West.

Amount: £3,850
Funder: The Wellcome Trust
Recipient: University of Warwick

Company surgeons, domestic life and medical practice in colonial India, 1750s-1850s 18 Jan 2010

This research on East India Company surgeons contributes to the PI's larger project on the role played by family structures in promoting British imperialism in India c. 1757-1857. It analyses the familial matrices that sustained imperialism and the ways in which social life shaped dominant systems of knowledge, including medical theories of race. Previous studies have demonstrated the contribution that eighteenth- and nineteenth-century East India Company surgeons made to the elaboration of new racial theories, upon which later nineteenth- and twentieth-century Western imperial expansion was to build. Extant research has focused on surgeons' use of new scientific tools, such as medical statistics and morbid anatomy, to address the health needs of male troops in India. This project expands beyond these perspectives, situating Company surgeons' racial theorizing within the two-fold context of their role as the medical attendants of white and mixed race colonial families and their aspirations for marriage, parenthood and financial independence. By assessing surgeons' theories of racial health alongside their experiences in India an man-midwives, family doctors, eligible bachelors and the fathers of children, this study reveals the myriad ways in which social and domestic life shaped the medical profession's scientific understanding in a colonial context.

Amount: £4,831
Funder: The Wellcome Trust
Recipient: University of Warwick

"The making of early modern scientific knowledge: Objects, spaces, practices and epistemologies" to be held at the University of Warwick on 2-3 July 2010 30 Nov 2009

This two-day symposium is the first UK-based attempt to bring together researchers working on knowledge production processes in Europe 1500-1800. The meeting has three main goals. Firstly, it will assess current 'state of play' in scholarship by fostering discussion amongst those working in varied aspects of the field. We aim to assemble an international group of scholars in various stages of their careers from a number of different disciplines including the history of medicine and science, global history and geography. Secondly, we will consider and assess a variety of early modern knowledge making processes, from informal experimentation to reading and writing natural philosophy, and the impact of these practices upon the development of medical and scientific knowledge. We will situate these processes within histories of early modern intellectual networks, histories of commerce, trade and consumption, histories of craft and artisanal skills and studies of experience and expertise. We will also focus upon broader issues such as the role played by gender, race and colonization upon knowledge production and dissemination. Finally, in terms of output, the meeting will generate a series of podcasts and a possible edited volume of essays.

Amount: £3,690
Funder: The Wellcome Trust
Recipient: University of Warwick

'Politics, policies and ethics of AIDS/HIV: Past and present' witness seminar/conference to held on 24 and 25 November 2009 at Warwick University 30 Nov 2009

The overarching objective of this interdisciplinary 2-day witness seminar/conference is to approach the history of AIDS/HIV from two different but intrinsically related methodological directions. Its goal is to comprehend, contextualise, reconstruct and convey the multifarious stories of this pandemic of the recent past and present. The witness seminar, a specialized form of oral history, brings together individuals whose long-term involvement in the fight against AIDS/HIV ranges across different national and international settings. It will offer space for participants to remember, discuss, debate, and even disagree about how AIDS/HIV shaped (and shapes) individual, institutional, national and international politics, policies and ethics. We will explore professional aspects of their work, as well as the reasons for their personal commitment. The seminar is also designed as a training-ground for future historians of medicine. A group of selected students, trained specifically in oral history by Prof Tilli Tansey, will interview and videotape the participants. · Building on the witness seminar, the one-day conference will unite its participants with international scholars working on the representations of AIDS/HIV arising from statistical data, archival, visual and literary materials. The conference objective is twofold: firstly, we will identify different forms of political engagement and health activism. Secondly, we will trace how and why these forms changed over time.

Amount: £7,225
Funder: The Wellcome Trust
Recipient: University of Warwick

"The transmission and communication of medical knowledge and services 1750-1900: The medical marketplace in the modern period." to be held in Venice on 5-6 March 2010 20 Oct 2009

This two-day workshop will explore the medical marketplace in (200 words) the modern period, particularly the transmission, communication and exchange of medical knowledge and services in regional, national and global settings. Participants will examine the transfer of techniques and knowledge in connection with specific diseases, illnesses and crises, as well as health care and regimen more broadly. The workshop aims to consider the implications these processes have for our understanding of the vibrancy of the medical marketplace in the modern period within and across geographical borders and spaces. By transmission we refer to exchanges involving medical practitioners, male and female, qualified and informal, as well as other agents, such as traders, travellers, migrant groups and patients. The two-day event aims to explore these topics comparatively in an international context, focusing on the period 1750-1900. It will incorporate new and path-breaking work on these themes, and involve established academics and early career researchers. We intend to follow up the workshop with the production of an edited volume.

Amount: £3,600
Funder: The Wellcome Trust
Recipient: University of Warwick

Biomedical Vacation Scholarship 14 Jun 2010

Not available

Amount: £2,880
Funder: The Wellcome Trust
Recipient: University of Warwick

Value in People Award. 29 Mar 2010

Not available

Amount: £200,000
Funder: The Wellcome Trust
Recipient: University of Warwick

The placental glucocorticoid barrier: regulation by corticotropin-releasing hormone (CRH) during inflammation. 27 Jan 2010

During human pregnancy, the placenta expresses complex machinery to dynamically control (and limit) fetal exposure to glucocorticoids. Since this system is sensitive to the actions of inflammatory molecules, we hypothesize that in pregnancies associated with inflammatory disorders, this placental glucocorticoid (GC) barrier might be specifically targeted and that placentally-derived corticotropin-releasing hormone (CRH) might play a key role in adaptation to dysregulated inflammatory responses. The aim of this project is to elucidate the role of CRH in the regulation of placental signalling machinery controlling GC bioactivity in normal placenta and how this system responds to states of inflammatory disease.

Amount: £70,000
Funder: The Wellcome Trust
Recipient: University of Warwick

The Arabic Version of Galen's On the Affected Parts : Edition and Study. 27 Nov 2008

The key goal is to establish a formal collaboration in the area of editing Arabic versions of Greek medical text between the Classics departments of the universities of Cairo and Warwick, both of which have a track record in this area. We specifically request funding enabling colleagues to visit the partner institution. Moreover, our joint project requires one PDRA, based at Cairo University, who will edit and study the Arabic version of Galen s On the Affected Parts. The Arabic version compris es some 90,000 words, and therefore constitutes a manageable amount of text to edit and study within the allotted time frame of 36 months. The edition will be based on a manuscripts selected according to the methods of textual criticism. The critical apparatus to be produced will record the major and significant variant readings, and indicate where they shed new light on the Greek text. The Arabic version, thus critically edited, will be entered into Arboreal, a database allowing researchers e asily to access and analyse texts in various versions and languages. The project will work mainly in Unicode and XML. A study will conclude the project and contribute significantly to questions of detail regarding medical history and Graeco-Arabic translation technique.

Amount: £26,453
Funder: The Wellcome Trust
Recipient: University of Warwick