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Paul Hamlyn Foundation
The Wellcome Trust
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PPE application: Researchers and Media for Public Engagement on Sickle Cell Disease in Tanzania. 22 Jun 2015

Severe anaemia is a major cause of morbidity and mortality in SCA. HbF is a major factor influencing anaemia, BT requirement and outcome. There is no information on HbF in East Africa. I propose to examine the association of HbF and severe anaemia in Tanzanian SCA patients. BT is the mainstay of management but concerns about safety, supply and cost have prompted a search for alternative interventions. Hydroxyurea is used in SCA in North America and Europe; effectively reducing morbidity (pain , hospitalisation, BT) and mortality. Its main efficacy is increasing HbF levels, but this has not been consistently reported. Other mechanisms include reduced inflammation and vasculopathy. There is inadequate information on its efficacy, mechanism of action and safety in Africa as it would be an alternative for BT. I will describe the response to hydroxyurea in SCA; determine the toxicity, optimal dosing and monitoring regime. In identifying patients for hydroxyurea treatment, I will dete rmine and treat known causes of severe anaemia such as infections (malaria, bacteraemia, parvovirus), splenic sequestration and nutritional deficiency (folic acid, vitamin A, B12, iron). This fellowship will provide the evidence on HbF and hydroxyurea required to conduct clinical trials and improve management of severe anaemia.

Amount: £125,021
Funder: The Wellcome Trust
Recipient: University of Leeds

Twentieth century disease ecologies: an intellectual history of emergence, 1920-1970 - Extension. 31 Mar 2015

Although the origins of the modern ecological understanding of infectious diseases has been examined by other scholars, for the most part these studies have focussed on specific groups of scientists and/or disciplinary settings. Moreover, preliminary studies of the subject are divided as to the extent to which these ecological perspectives were already present in medical micribiology as opposed to being importation from biology and molecular genetics. There is a need therefore for a comprehensiv e, monograph-length study that surveys the history of ecological perspectives across a range of disciplines from bacteriological epidemiology, to evolutionary biology, parasitology, animal ecology and immunology, and across a broader group of scientific researchers. In particular, this study will build on the preliminary surveys of this field by Anderson, King, Mendelsohn, and Tilley (see bibliography) by tracing the intellectual influences and professional associations between scientists at the forefront of research into epidemic diseases in the interwar and post-war periods. At the same time it will examine the connections between these scientists and key public health institutions, such as the Rockefeller Foundation and the Hooper Foundation, and the effect that post-war debates around the eradication of infectious diseases and environmental politics had on these nascent ecological perspectives

Amount: £51,748
Funder: The Wellcome Trust
Recipient: Queen Mary University of London
Amount: £750,000
Funder: The Wellcome Trust
Recipient: Save the Children
Amount: £58,249
Funder: The Wellcome Trust
Recipient: University of Oxford
Amount: £148,505
Funder: The Wellcome Trust
Recipient: University of Leeds

Modernist Children. 19 May 2015

Not available

Amount: £5,790
Funder: The Wellcome Trust
Recipient: University of Manchester
Amount: £8,949
Funder: The Wellcome Trust
Recipient: Glamorgan Archives

Care of last resort? : York Poor Law Union and Workhouse, 1835-1963 - Scoping Grant 31 Mar 2015

Explore Ypork Libraries and Archives ('Explore') seeks a scoping grant to engage the expert skills and advice of a consultant archivist and conservator. These consultants will produce a collections managemnt report to inform and enable a bid to the Wellcome Trust's Research Resources fund for the proposed 'Care of last resort? : York Poor Law Union and Workhouse' project.

Amount: £11,000
Funder: The Wellcome Trust
Recipient: Explore York Libraries and Archives

Gonadotrophin releasing hormone receptor antagonists: a novel treatment for ectopic pregnancy 24 Jun 2015

Ectopic pregnancies (EP) represent 1-2% of pregnancies and are a leading cause of maternal morbidity and mortality. 60% of EP currently require surgical management but progressively earlier diagnosis is allowing more women to choose medical management with systemic methotrexate. However, methotrexate treatment requires prolonged follow-up, has significant side effects and fails in 30%, which then necessitates surgery. I propose that gonadotrophin releasing hormone receptor antagonists (GnRHR-ant ), drugs currently licensed for infertility treatment in women with few side effects, may offer an alternative EP treatment for the following reasons. GnRH and its receptor (GnRHR) are expressed by placenta-forming trophoblast cells. My pilot data confirms EP trophoblast GnRHR expression and shows that GnRHR-ant inhibit trophoblast proliferation in culture. Moreover, GnRH controls trophoblast human chorionic gonadotrophin (hCG) production, the critical endocrine support of an early pregnancy. Th us, I plan to investigate the effect of GnRHR-ant on trophoblast proliferation, invasion and hCG production in-vitro; using human and immortalised trophoblast cells and a novel trophoblast-oviduct co-culture; and in-vivo using a human trophoblast xenograft model and a fetal resorption mouse model. I will increase our knowledge of trophoblast biology and aim to provide sufficient evidence to support a clinical trial using GnRHR-ant to treat EP.

Amount: £237,155
Funder: The Wellcome Trust
Recipient: University of Edinburgh

Investigation of Syndecan-2 selected purified human umbilical cord mesenchymal stromal cells as a novel therapy for liver fibrosis. 24 Jun 2015

The aim of this project is to examine the ability of purified syndecan-2 (SDC2)-selected human umbilical-cord mesenchymal stromal cells (MSC) to resolve established fibrosis, thus determining their potential as a clinical treatment for patients with advanced liver fibrosis. I will firstly determine the effect of SDC2-selected MSC on the resolution of liver fibrosis by injecting them into 3 different murine models of established liver fibrosis. I will explore the mechanistic role of SDC2 ex pression by use of MSC with up- and down-modulated SDC2 expression (achieved by adenoviral transfection), in a model of CCl4-induced fibrosis. I will determine how SDC2-expression affects the anti-fibrotic phenotype by comparing the secretory cytokine signature of cultured MSC after modulation of SDC2 expression. I will then establish how SDC2-selected MSC affect murine hepatic stellate cells (HSC) in a model of CCl4-induced fibrosis by the use of transgenic hepatic stellate cell reporter mic e This will allow co-localisation of HSC with labelled MSC to be studied, and also cell sorting of HSC to determine their fate and activational status. I will subsequently use selective cytokine neutralisation during co-culture of MSC with murine and human HSC to ascertain the MSC effectors that determine HSC function.

Amount: £265,946
Funder: The Wellcome Trust
Recipient: University of Birmingham

Harnessing the immune response in chronic HBV infection to optimise current treatment strategies. 26 Feb 2015

We have shown that Pegylated-Interferon-alpha (Peg-IFN-aplha) expands activated NK cells with restored antiviral effector potential. These innate effects are not seen with Nucleos(t)ide analogues (NUCs), but T-cell restoration has been demonstrated with NUCs. We hypothesise that complementary innate/adaptive immune boosting can be achieved in patients receiving sequential NUCs following Peg-IFN-aplha exposure. Although the antiviral function of NK cells is restored with Peg-IFN-aplha, we postula te the documented increase in expression of the death ligand TRAIL promotes deletion of HBV-specific T-cells expressing the TRAIL-R2 receptor. We will dissect the temporal dynamics of T and NK cell reconstitution and examine whether TRAIL blockade enhances the efficacy of Peg-IFN-alpha/sequential NUC therapy by protecting antiviral T-cell responses from deletion. We will use PBMC and fine needle liver aspirates from patients undergoing therapy to determine if innate boosting and restoration of T-cell responses are optimised on sequential NUC therapy. We will perform functional experiments in vitro, with TRAIL blocking antibodies and NK cell depletion to rescue Peg-IFN-alpha driven killing of T-cells. TRAIL pathway manipulation may boost adaptive immunity by interrupting NK cell-mediated deletion of T-cells in the face of innate boosting, with the goal of achieving sustained responses with a finite treatment duration.

Amount: £233,956
Funder: The Wellcome Trust
Recipient: Queen Mary University of London

Molecular mechanisms and therapeutic strategies in amyotrophic lateral sclerosis caused by mutations in the C9orf72 gene. 26 Feb 2015

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterised by motor neuron degeneration. A hexanucleotide expansion in the C9orf72 gene is a common cause of ALS and my supervisors (Isaacs and Partridge) recently published evidence from a Drosophila model in the journal Science that neurotoxicity is mediated by dipeptide repeat (DPR) proteins generated by repeat-associated non-ATG translation. Emerging evidence suggests that DPR proteins cause nucleolar dy sfunction and resolving this in relevant disease models will significantly increase our understanding of and ability to treat C9orf72-ALS. Aims: Using C9orf72-ALS models I will evaluate if DPR proteins cause nucleolar dysfunction and interact with RNA and whether promising novel small molecules which bind C9orf72 repeat RNA reduce DPR formation, nucleolar dysfunction and neurotoxicity. Methods: I propose a carefully integrated approach that will combine assessment of nucleolar function an d therapeutic potential of the small molecules in 1) novel in vivo Drosophila models, with subsequent validation in 2) C9orf72 mutation human induced pluripotent stem cell (iPSC)-derived spinal motor neurons. This approach across model systems will serve to rigorously validate the findings made. Implications: These experiments may provide novel mechanistic insights into a common form of ALS and deliver pre-clinical data on an exciting therapeutic approach.

Amount: £250,511
Funder: The Wellcome Trust
Recipient: University College London

Anopheles-Plasmodium interactions: mosquito immune response and parasite immune evasion strategies. 07 Jul 2015

Malaria parasites entering the mosquito midgut are eliminated by robust mosquito immune reactions, and only few remain to continue the transmission cycle. My principal research questions are: how mosquito immune reactions are activated on parasites and how some parasites evade these reactions. By answering these questions, I aim to gain fundamental understanding of the Anopheles-Plasmodium interactions leading to disease transmission. This knowledge could aid future translational research for th e development of malaria transmission-blocking interventions, contributing to the global effort for malaria elimination.

Amount: £20,930
Funder: The Wellcome Trust
Recipient: Wellcome Trust Sanger Institute

The host response to Staphylococcus aureus infection. 01 Apr 2015

How is the host response to Staphylococcus aureus orchestrated? How does S. aureus trigger release of nerve growth factor (NGF) from host cells? How does NGF trigger host effector immunity to S. aureus?

Amount: £121,000
Funder: The Wellcome Trust
Recipient: Wellcome Trust Sanger Institute
Amount: £34,700
Funder: The Wellcome Trust
Recipient: Imperial College London

The Corpse Project Phase 1. 17 Sep 2015

The Corpse Project aims ultimately to improve options for the body after death, through multidisciplinary research and public engagement. Our starting points are that burial and cremation as currently practiced are, generally, poor versions of ancient practices and fail to return the body to the natural cycle. The environmental implications of current and alternative practice are under-researched and poorly understood. This matters, given threats to soil health and wider ecosystems pressures. As important, the UK seems particularly affected by a loss of rituals around, and acceptance of, the dead body, which have historically provided a way to mourn, and to be reconciled to, death. The Corpse Project will aim to establish whether human and ecological well-being can benefit from a more open and informed consideration of the corpse. For the development year, key goals are: 1. Public knowledge and attitudes to the treatment of the corpse and 'ashes' surveyed, to include young pe ople and diverse communities. 2. Literature review (ecosystems and cultural). 3. Public exhibits around decomposition developed. 3. Networking, policy checking and other activity to prove project concept and build sustainability of future work (see below).

Amount: £48,910
Funder: The Wellcome Trust
Recipient: The Corpse Project