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Results

Investigating the Structure of FcγRIIa and its Interactions within the Membrane 30 Sep 2018

Human Fcgamma receptors (FcgammaRs) are proteins found on the surface of immune cells. They bind to antibodies, which are produced by the body, in response to infection. Some antibodies produced recognise their own tissues and are found in many diseases, including rheumatoid arthritis and lupus. It has been shown that genetic changes in the FcgammaRs are found more frequently in rheumatoid arthritis sufferers compared to healthy individuals. This project will focus on FcgammaRIIa, which is present on cells which are responsible for the destruction of many antibody-bound objects. Through a combination of cutting edge techniques, spanning physics, biology, immunology and medicine, we will uncover fundamental information within this field. This information would aim to inform the production of effective therapies to treat diseases such as arthritis, which put a huge strain on the NHS every year.

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

A structural investigation into the action of and resistance to ribosome-targeting antibiotics 30 Sep 2018

Antibiotics are crucial to modern medicine, allowing treatment of life-threatening bacterial infections and making many surgeries like transplantations possible. However, pathogenic bacteria are rapidly evolving to resist their effects. Protein synthesis is one of the main antibiotic targets in bacterial cells. I will use structural biology techniques, principally cryoEM and single particle image processing, to understand how both novel natural products and clinical antibiotics bind to the ribosome to bring about their inhibitory effects on protein synthesis. Furthermore, I will investigate the cause of toxicity of certain ribosome-binding antibiotics by examining how they bind to the mammalian mitochondrial ribosome. Finally, I will use a combination of cryoEM and protein X-ray crystallography to elucidate how certain ribosomal-protecting proteins form complexes with the ribosome in order to bring about antibiotic resistance. On an individual level, these studies will allow an assessment of the viability of novel natural products as suitable clinical antibiotics. More generally, they will contribute to our knowledge of how different classes of antibiotics target the ribosomes of pathogenic bacteria, and how these bacteria evolve resistance. This knowledge will help the development of methods to rationally design new ribosome-targeting antibiotics that are able to overcome or circumvent resistance.

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

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

Functional characterization of a novel KMT2D-related developmental disorder 31 May 2018

The proposed research uses standard molecular biology, protein purification and biophysical structural analysis methods in a focused series of experiments that comprise a complete 6-week project. This builds on existing molecular genetics studies that have identified novel missense mutations in KMT2D (also known as MLL2) as the cause of a unique phenotype (renal tubular dysgenesis, choanal atresia and athelia). Previous studies have identified KMT2D mutations as a major cause of Kabuki syndrome, a comparatively common autosomal dominant congenital mental retardation syndrome. The missense mutations occur in a central region of the KMT2D protein (2841-3876) that does not have variants associated with Kabuki syndrome. This central region contains a series of coiled-coil domains that are likely to mediate protein-protein interactions. However, the effect of the missense mutations on KMT2D structure and interactions is completely unknown. This project will determine the structure-function relationships between KMT2D and a unique phenotype that are likely to be caused by altered protein-protein interactions, as well as describing the broader genotype-phenotype correlations in this important gene. The approach described in the proposal is the only tractable way to understand possible structure-function relationships, given the large size of the gene and encoded protein.

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

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

Revealing how extracellular matrix glycans define chemokine gradients 31 May 2018

The diffusion of chemokines in the extracellular matrix is a requirement for the formation of chemokine gradients that guide immune cell migration to sites of inflammation, and controlled by matrix glycans of the glycosaminoglycan family. The focus of this research is to use well-defined models of the extracellular matrix to probe the interaction between the chemokine CXCL12 and the glycosaminoglycan heparan sulphate, and how this defines the mobility of CXCL12. The first key goal of the project is to design and produce a fluorescently-tagged CXCL12 mutant with modulated glycosaminoglycan binding which can be compared against the wild-type chemokine and other mutants already available. The second key goal is to use the biophysical method of fluorescence recovery after photobleaching to characterise the differential diffusion of mutant and wild-type CXCL12 in glycosaminoglycan-rich matrices. This project thus combines biochemistry and biophysics to gain a better understanding of the molecular mechanisms underpinning the formation of chemokine gradients in extracellular matrix.

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

Specialised Ribosomes – Does KSHV modulate ribosome composition 30 Sep 2018

Historically, ribosomes have been viewed as unchanged homogeneous units with no intrinsic regulatory capacity for mRNA translation. Recent research is shifting this paradigm of ribosome function to one where ribosomes may exert a regulatory function or specificity in translational control. Emerging evidence has identified heterogeneity of ribosome composition in specific cell populations, leading to the concept of specialised ribosomes. Specialised ribosomes may therefore exhibit control and regulation over the translation of specific mRNAs, resulting in a substantial impact on how the genomic template is translated into functional proteins. Due to the emerging concept that cells can control the composition of ribosomes to regulate protein expression, it would seem highly likely that viruses could also manipulate host cell ribosome compositions to enhance the production of viral proteins. We have quantitative proteomic and ribosomal profiling data suggesting Kaposi's sarcoma-associated herpesvirus (KSHV) manipulates ribosomal biogenesis. Firstly, we will investigate changes in composition and stoichiometry of proteins within the ribosome, driven by KSHV. We will isolate ribosomal complexes by tandem affinity purification, during KSHV infection and analyse changes by LC-MS/MS and cryo-EM. We will elucidate how these changes exert ribosome-mediated specificity to promote KSHV lytic infection using a number of cellular and molecular techniques.

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

Understanding the role of retinoic acid in cyanobacteria 31 May 2018

We will be investigating the viability of using cyanobacteria as a model for our own by exploring the evolutionary links as well as the similarities between human cells and cyanobacteria cells in terms of the communication and cell differentiation. This will allow us to use the cyanobacteria as a model for human stem cells. There are 3 cases which will be investigated: metabolism of retinoic acid, nitrogen-fixing cells and prostaglandin cell signalling. In each case, we will be blocking the signal, modifying the bacteria and studying how this affects the bacteria. The production of proteins and the chemical signalling are amongst the several responses we will be monitoring. Using information gained from this we will be able to see if there is a viable link that can be used to monitor cyanobacteria that have human orthologues spliced into it.

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

Grb2-mediated regulation of miRNA maturation in the basal state. 30 Sep 2018

Cancers develop as a result of many interacting factors. Two such factors are cell stress and microRNA (miRNA) expression. Cell stress causes fluctuations in protein levels, which can perturb the proper functioning of the cell. miRNAs silence specific genes, and therefore can induce changes within the cell which cause them to become cancerous. However, little is known about how miRNA expression is altered. I aim to investigate a novel mechanism of miRNA regulation, which may be perturbed by cell stress. I will determine how the levels and activity of key components in miRNA biogenesis are altered in cells expressing different proteins and which have been subject to different stress conditions, using a range of in vitro, cell-based and biophysical approaches. I will also perform several screens to identify key microRNAs regulated by this mechanism, and how their expression changes with cell stress. This work will reveal new avenues for cancer therapy and help us to target cancer with a fresh perspective.

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

Brain regulation of feeding behaviour through mitochondria fission 21 May 2018

Obesity causes brain insulin resistance and prevents the brain from regulating metabolic responses, maintaining energy balance and controlling the nutritional status of an individual. Restoring the brain’s ability to modulate metabolic functions could be an important intervention to prevent the negative outcomes of obesity and diabetes. The Dorsal Vagal Complex (DVC) in the brainstem senses insulin to regulate glucose metabolism, food intake and body weight in rodents. Three days of high-fat diet feeding is sufficient to completely disrupt the insulin response in the DVC, thus causing an increase in blood glucose levels and excessive eating. Recently, I discovered that increased mitochondria fission and ER stress in the DVC can cause insulin resistance and affect the ability of the DVC to regulate blood glucose levels. I aim to understand whether increased mitochondria fission in the DVC can affect food intake and body weight in rats. Using in vivo and in vitro experiments, I aim to uncover the mechanism by which changes in mitochondria shape and size affect DVC insulin sensing and eating habits in rodents. This project could lead the way for the development of novel approaches that target the brain to regulate food intake and body weight in obese subjects.

Amount: £99,948
Funder: The Wellcome Trust
Recipient: University of Leeds

Peripheral gate in somatosensory system 17 Jul 2018

Peripheral nerves are responsible for haptic, somatic and visceral sensations including that of pain. Healthy nerves conduct action potentials from their peripheral endings to the dorsal spinal cord, where synaptic transmission first takes place. It is assumed that the peripheral somatosensory signals are first integrated in the spinal cord and subsequently analysed in the brain. Our recent findings has challenged this view and suggested that peripheral somatosensory ganglia (such as dorsal root ganglia, DRG) are capable to regulate pain transmission utilising GABAergic somatic cross-talk mechanisms. I hypothesize that somatosensory ganglia represent a new type of a ‘gate’ within the somatosensory system. My overarching goal is to develop a comprehensive mechanistic understanding of the peripheral somatosensory gating. I will use in vivo electrophysiology, mouse transgenics, chemo- and optogenetics, behavioural models and other cutting-edge approaches to address the following specific aims. (1) Secure direct in vivo evidence for peripheral somatosensory integration at the DRG. (2) Moving beyond GABA: identify other major ganglionic communication mechanisms. (3) Elucidate physiological context of signal integration in the DRG. (4) Identify subcellular structures involved in somatic integration. These studies will change current understanding of somatosensory processing and will provide new ideas for pain treatment at the periphery.

Amount: £1,141,006
Funder: The Wellcome Trust
Recipient: University of Leeds

Non-genetic oncogenesis in adenocarcinoma of the oesophagus and gastro-oesophageal junction: characterising the stress-inducible FGFR2-GRB2-miRNA axis. 30 Sep 2018

Oesophageal adenocarinoma (OAC) is a type of cancer affecting the lower part of the oesophagus (the gullet). The number of patients diagnosed with OAC has increased substantially over the past three decades. As a result, OAC is now the most common type of cancer affecting the oesophagus. Unfortunately, there are currently few effective treatments for OAC. Many patients with OAC will however first be diagnosed with Barrett's oesophagus. This is a condition in which the normal lining of the lower oesophagus becomes glandular and starts to grow abnormally. It is not clear why this happens but it may be related to reflux of stomach contents (such acid and bile) into the oesophagus (as happens in patients who frequently experience heartburn). Our research suggests that bile and acid may be able to change the concentrations of proteins within the glandular cells. The altered levels of these proteins may then contribute to the cells becoming cancerous. This work will look to see if this is the case and ma help us to find new drug targets to prevent and treat Barrett's and OAC.

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

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

Modulating protein activity using peroxisomal re-localisation 30 Sep 2018

The majority of small molecule drugs on the market only target a very small range of potential targets. They function by their binding event causing a direct modulation of their target protein’s function, however it is not clear that all proteins involved in disease can be targeted in such a manner. In this project, I aim to develop drug molecules with a different mechanism of action. One half of the molecule will be able to bind to a protein involved in a disease pathway and the second half of the drug would be capable of dragging the molecule to an enclosed cell compartment, known as the peroxisome. Such re-localisation will trap the disease pathway associate protein making it unable to carry out its function providing a new strategy for therapeutic intervention.

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

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

Lead identification of a novel anticoagulant agent targeted against activated factor XII for the prevention of thrombosis without the risk of bleeding associated with current antithrombotics 01 Oct 2017

At the University of Leeds, Dr Helen Philippou (PI) and Prof Robert Ariens (Faculty of Medicine and Health), with colleagues (Faculty of Mathematics and Physical Sciences) Dr Richard Foster and Prof Colin Fishwick with Prof Gregory Lip (University of Birmingham) have secured a £3,021,002 Wellcome Trust Seeding Drug Discovery award to develop new safer anticoagulants with minimal risk of bleeding. The medicines available to treat patients who suffer from an increased risk of blood clotting are effective but carry a significant risk of causing bleeding. Current treatments therefore involve a balance between reducing blood clots with inducing bleeding. The objective of this proposal is to discover highly specific compounds which block a protein, Factor XIIa, which is involved in clot formation, and for which there is good evidence to suggest inhibition will not cause bleeding. This will allow patients to be treated more safely with minimal risk of bleeding without needing therapeutic monitoring. The aim is to produce an agent which will be given by mouth daily.

Amount: £86,457
Funder: The Wellcome Trust
Recipient: University of Leeds

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 Awards 2017/18 30 Sep 2018

Not available

Amount: £35,284
Funder: The Wellcome Trust
Recipient: University of Leeds

Open Access Award 2017/18 30 Sep 2018

Not available

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