- Total grants
- Total funders
- Total recipients
- Earliest award date
- 10 Apr 2001
- Latest award date
- 30 Sep 2018
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
Grant awarded to Community Service Volunteers (Training and Enterprise NE) (Tyne & Wear) 10 Mar 2009
To provide support and mentoring to people with mental health problems to help them volunteer in Newcastle.
Grant awarded to Community Service Volunteers (Training and Enterprise NE) (Tyne & Wear) 13 Jul 2004
To provide daycare services to older people living in high rise flats in Newcastle.
Positive Futures London 18 Nov 2015
This project, based on a established youth-led volunteering model is expanding as a result of self-referrals and is being delivered in Hackney, Haringey and Tower Hamlets. It will support young people aged 13 to 25 to deliver volunteering and social action projects which they have identified to be of benefit to the local community. The aim of project is that all of the young people who are participating in it will develop key skills and have positive experiences that will shape their personal development.
Characterisation of PI3K signalling in response to Streptococcus pneumoniae infection using zebrafish larval model 31 May 2018
Immunomodulation is a novel approach to treating infections that could be used to limit the use of antimicrobials which have become less effective due to antibiotic resistance. Regulating the innate immune response via targeting specific immune signalling may help to boost bacterial clearance without causing excessive tissue damage. One of the pathways involved in innate immune regulation is phosphatidylinositol 3-kinase (PI3K) signalling. Different classes of this kinase have been shown to be involved in phagocytosis, ROS production and antibacterial autophagy, among other processes. Therefore, PI3K is an attractive target for therapeutic immunomodulation. In this study, using zebrafish larval infection model, several different PI3K inhibitors will be tested in a chemical screen to identify the role of specific PI3K isoforms in Streptococcus pneumoniae infection. Our aim is to identify compounds that would affect survival of infected zebrafish and bacterial CFU counts in vivo. The effect of hit compounds on phagocytosis and ROS production in response to infection in vivo will be further tested using fluorescence and confocal microscopy. This project will elucidate the mechanisms that govern signalling in neutrophil and macrophage responses to infection and investigate into a prospective target for immunomodulatory treatments.
Investigating drugs which promote neutrophil apoptosis for the treatment of inflammatory disease 31 May 2018
Chronic Obstructive Pulmonary Disease (COPD) is a progressive and irreversible inflammatory lung condition which affects 10% of the world’s population. The pathogenesis of this disease centres around inappropriate neutrophilic persistence in the lungs due to dysregulation of apoptosis, which results in injury and ongoing cycles of inflammation. Current therapeutic strategies treat the symptoms of the disease but not the underlying cause, and long-term use leads to significant side effects. We are therefore in great need for more effective medications to treat COPD. The Prince group carried out genetic kinase screens and inhibitor assays to search for novel treatments for inflammatory diseases. They identified members of the ErbB family of receptor tyrosine kinases, which play a role in regulating neutrophil cell survival and inflammation in vivo, as targets. Various ErbB inhibitors have already been approved as medicines for the treatment of cancer and could be repurposed for COPD. This project will investigate firstly whether clinically-used ErbB inhibitors have the same apoptosis-driving effect as the research grade inhibitors with which preliminary research was carried out, and secondly whether these drugs impact the immune response to Haemophilius influenzae. This is important because COPD patients are often chronically colonised with microorganisms, including H. influenzae.
The expression of the tumour suppressor gene, E-cadherin, has been found to be positively correlated with the expression of 31 human genes, which have 14 Drosophila homologues. Six of the Drosophila genes are not known to regulate/be regulated by E-cadherin. The aim of this project is to investigate whether E-cadherin regulates the expression of two top candidate genes, fusilli and grainy head, or conversely, if E-cadherin is regulated by them. In order to determine whether fusilli and grainy head regulate E-cadherin, expression of these genes will be downregulated with RNAi using the GAL4-UAS system in Drosophila, and the changes in E-cadherin amounts and localization will be quantified. Simultaneously, E-cadherin will be acutely overexpressed using GAL4-UAS in combination with the temperature-sensitive GAL4-inhibitor GAL80 in order to test if it has an effect on the expression of fusilli and grainy head. Changes in expression will be determined using RT-qPCR. Altogether, this project aims to reveal novel regulators or effectors of E-cadherin.
In a search for alternative antibiotic therapeutic approaches, innovative strategies that aim to modulate host components essential for infection have come to prominence. Many Gram-negative and Gram-positive pathogens such as Pseudomonas aeruginosa and Staphylococcus aureus utilise host microdomains formed by the tetraspanin superfamily of transmembrane proteins as an adhesion platform and a gateway for infection. Bacterial adherence is thus considered an essential step for colonisation and infection, and in 65-80% of cases, this leads to the formation of bacterial communities (biofilms). Such infections are difficult to eradicate as biofilms provide a protective mode of growth. The project proposed herein aims to test the efficiency of a library of anti-adhesion peptides that specifically target tetraspanin-enriched microdomains in a biofilm infection model. To achieve this, an in-situ representative biofilm infection model (harbouring P. aeruginosa and/or S. aureus) will be established on the surface of human-derived skin cell lines, namely keratinocytes. Biofilm development will be analysed using the BioFlux, confocal microscopy and bacterial counting. The efficiency of tetraspanin-derived peptides will then be tested; with the aim of determining if this therapy prevents biofilm formation, disrupts existing biofilms or enhances the efficacy of conventional antibiotics. Keywords: biofilm infection model, anti-adhesives, host-pathogen interaction, tetraspanins.
How Does the Interplay of PI3-kinases at the Phagosomal Membrane Co-ordinate Pathogen Killing? 30 Sep 2018
Animals (including humans) are protected from bacterial infection by patrolling innate immune cells. Neutrophils (the most abundant phagocytes) engulf their prey into membrane-bound phagosomes, enabling targeted, segregated and highly concentrated microbicidal activity. Phosphoinositide 3-hydroxykinase (PI3K) signalling regulates many aspects of neutrophil function and PI3K-derived phospholipid mediators accumulate at the phagosomal membrane to facilitate killing. However, the identity of the PI3K isoform(s) involved, the mode of delivery to the phagosome, and the extent to which pathogens subvert this process have not been determined. Our novel preliminary data show that the lipid messenger PIP3 (a product of PI3K activity) waxes and wanes at the phagosomal membrane, reflecting ‘quantal’ delivery from an unidentified cellular organelle, with subsequent changes in phagosomal pH. I will undertake a detailed exploration of this critical process using the genetically tractable zebrafish, which allows high resolution in vivo imaging of neutrophils in relevant infection models. I will determine the dynamics of PI3K signalling in response to a range of pathogens,quantifying PI3K-derived phospholipids at the phagosomal membrane. My results will inform our knowledge of PI3K signalling in neutrophil bactericidal activity, and may suggest how these processes might be manipulated to enhance pathogen killing.
The Wellcome Trust Doctoral Training Centre in Public Health Economics and Decision Science (PHEDS) 30 Sep 2017
Development of selective Adrenomedullin-2 receptor antagonists for the treatment of pancreatic cancer 05 Dec 2016
Pancreatic cancer is the 10th most common cancer, but in the next 15 years, it will become the second highest cause of cancer-related death. Unlike almost all other cancers, the prognosis has not changed in the last 30 years. After diagnosis, outcomes are very poor, with 1-year and 5-year survival rates of <25% and <5% respectively. The best current therapies offer only a few months of increased life expectancy, and patients’ quality of life is poor despite palliative treatments. There is clearly a pressing need for better treatments for pancreatic cancer. In 2015 a team from the University of Sheffield led by Professor Tim Skerry, with Peakdale Molecular and Sandexis Medicinal Chemistry was awarded Seeding Drug Discovery funding. They received just under £3M to develop selective antagonists of the adrenomedullin-2 receptor. Adrenomedullin is a hormone involved in cancer growth and spread, which also has important roles in the control of blood pressure. Adrenomedullin acts through two different receptors one of which mostly regulates blood pressure. The other has important roles in cancer biology. The team have shown that in model systems, blockade of the receptor reduces tumour growth and spread. They have developed novel lead compounds to block the adrenomedullin-2 receptor and inhibit its important roles in cancer, while keeping its normal functions.In 2017 a further award of up to £2M was made to the team of Skerry, Richards and Harrity to support further medicinal chemistry and compound development with a view to nominating by mid 2019, a candidate drug for regulatory approvals prior to clinical trials.
Determining the mechanisms regulating immune-directed clearance of senescent cells to promote healthy ageing 22 Feb 2017
The number of people over the age of 65 is predicted to double by 2060, accompanied by an increase in chronic diseases, which already consume up to 80% of healthcare costs. Developing therapies for chronic ageing diseases is, therefore, an urgent priority. A key driver of ageing diseases is telomere dysfunction and consequent cell senescence. Genetic ablation of senescent cells ameliorates diseases of ageing in mice, highlighting senescence as a promising therapeutic target. The immune system clears senescent cells, but with ageing, senescent cells accumulate causing disease. The mechanisms regulating senescent cell clearance in telomere-dependent ageing in vivo are unknown. I will test the hypothesis that senescent cells are not cleared with ageing due to telomerase-dependent dysfunction of the immune system. I will use the premature ageing telomerase mutant zebrafish I developed, which age in a telomere- dependent manner, and are exceptionally amenable for imaging and genetic manipulation. I will determine which leukocytes clear senescent cells in aged tissues in vivo, identify the key mechanisms involved and determine how these change with ageing. I will then test whether manipulation of these targets is sufficient to prevent or delay tissue degeneration and frailty in old zebrafish.
Vacation Scholarships 2017 - University of Sheffield
Mathematical skills predict career outcomes, health literacy, and finance skills. Troublingly, almost half of the adult population in the UK have a mathematical skill level equivalent to primary education. In order to remediate this and design effective, early interventions, it is important that we first understand how mathematical skills develop. In particular, little is currently known about the cognitive skills underlying mathematical skills. We will focus on understanding word problems because this is the type of mathematical information people more commonly encounter in daily life. We are interested in how high-level cognitive skills (known as executive functions) and language skills help solve mathematical word problems in children ages 5 and 6 – the age at which children first start formal schooling. Furthermore, since little attention has been placed on different types of word problems, we propose to investigate specifically which cognitive skills 5 to 6 years-old children use while solving ‘consistent problems’ (word problems involving relational terms that are consistent with the required mathematical operator) and ‘inconsistent problems’ (relational terms conflicting with the required mathematical operator). Findings will contribute to our understanding of how children acquire complex problem-solving skills and offer guidance on where to focus educational and interventional effort.
Elucidating the role of a potential new therapeutic target to inhibit RAN translation in C9ORF72-ALS-driven neurodegeneration 27 Apr 2017
The most prevalent form of familial Motor Neurone Disease (MND) is caused by a hexanucleotide repeat expansion (HRE) of the C9ORF72 gene. This hexanucleotide sequence (GGGGCC) is within a non-coding region of the first intron of the C9ORF72 gene with repeat expansions of this sequence ranging from 50 to thousands of repeats. This HRE results in the generation of a guanine rich nucleic acid capable of forming stable G-quadraplex structures. Interactions of this G-quadraplex structure with RNA-processing factors allows the HRE to undergo Repeat-Associated Non-ATG-dependant (RAN) translation, an abnormal translation initiation event occuring in the absence of a start codon. RAN translation can occur from the sense or antisense strand and in all three frames, leading to the production of 5 different dipeptide repeat (DPR) proteins. It has been implicated that aggregation of these DPR proteins is responsible for motor neuron toxicity and accounts for the neurodegeneration seen in MND. This project aims to explore the role of eukaryotic translation initiation factor 4B (eIF4B) in RAN translation of the C9ORF72 HRE. eIF4B knockdown will be achieved through RNAi and the subsequent effects of this on DPR production and cell proliferation will be investigated using Western Blotting, Immunofluorescence and MTT assays.
Determining Novel SMURF1 Signalling Pathways and Precision Medicine Strategies in Patients with Pulmonary Arterial Hypertension 25 May 2017
Pulmonary arterial hypertension (PAH) is a rare, but devastating disease that leads to increased pulmonary vascular resistance, right heart failure and death. Despite clear clinical and biological differences between individual patients with PAH the treatment is uniform, based on an algorithm that matches the number of vasodilator drugs to functional class. I aim to establish SMURF1 inhibition as a novel anti-proliferative therapy and pathway for precision medicine for patients with PAH. I have demonstrated that SMAD-specific ubiquitin ligase regulatory factor-1 (SMURF1) is critical to pulmonary vascular remodelling and experimental PAH, and that SMURF1 mRNA expression is detectable and increased in peripheral blood from patients with PAH. In November 2015 my collaborators (Novartis) patented a series of SMURF1 inhibitors. Through this Fellowship I will use cutting edge RNA and protein profling techniques to determine mechanism though which SMURF1 mediates disease pathology and, using samples and clinical data from the worlds largest and best genotyped-phenotyped cohort of patients with PAH (the UK National Cohort), investigate means of identifying patients with cellular abnormalities related to SMURF1 who may benefit from a SMURF1 targeted therapy.
Manipulation of host hypoxia signalling as a therapeutic strategy for mycobacterial infection 29 Oct 2014
Therapeutic strategies that target pathogens are failing and TB has re-emerged as a leading cause of global mortality with 1.3 million deaths yearly (WHO, 2012). There is an unmet need for novel, host-targeted therapeutics that upregulate the immune response to infection to complement current antimicrobials. Tissue hypoxia is a potent activator of leukocyte responses via activation of host hypoxia inducible factor (HIF) signalling. I hypothesise HIF signalling is a host-response that if therapeu tically activated, will improve the host response to infection. My overarching aim is to test this hypothesis in vivo. In a zebrafish mycobacterial infection model, I have shown that genetic upregulation of HIF prior to infection leads to higher levels of bactericidal nitric oxide in neutrophils and to reduced burden of infection. These data support an emerging paradigm where neutrophil killing of mycobacteria is essential for disease control and identify HIF and NO as effective targets for int ervention against mycobacterial infection. Combining genetic approaches with dynamic live-imaging, I will address the following hypotheses: 1) HIF activation is a host antibacterial response that is actively downregulated by Mm at a critical tipping-point of infection; and 2) Pharmacological upregulation of leukocyte Hif is a viable therapeutic strategy for mycobacterial infection.
Validation and Models in Computational Biomedical Science: Philosophy, Engineering and Science 20 Jul 2015
With this workshop we will raise the profile of medical humanities as a contributor to the ongoing development of scientific technologies, methodologies and tools that have a strong impact on shaping biomedical science and practice. The particular focus of the workshop is the key epistemological topic of model validation, which is of common concern to scientists, clincians, engineers and philosophers, and crucial to the effective implementation of computational modelling and simulating in biomedical application areas. The central questions to be jointly addressed are: how are models evaluated and assessed in the different contexts of computational medicine, do differences in conceptions give rise to obstacles in translation across sectors, and how do approaches to model validation affect potential biomedical practice in the clinic and in health care more broadly? Throughout we will focus on issues of cross-disciplinarity and in particular the role of philosophy and social science in mediating between different conceptions of model validation. The workshop will be used to intiate a roadmap for future work on complementary perspectives on computational biomedical science, and in particular, will inform a major collaborative grant proposal.
The Repair of Oxidative and Topoisomerase Induced Chromosomal Breaks: Mechanisms and Implications for Human Health. 01 Apr 2014