- 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.
Synthesis, characterisation and biological evaluation of a novel library of iminosugar compounds as inhibitors of Galactofuranosyl Transferase 2 inhibitors in Mycobacterium Tuberculosis 30 Sep 2018
The increasing prevalence of antimicrobial resistance (AMR) represents one of the greatest existential to humanity. Of particular concern is the emergence of multi-drug and extensively drug-resistant tuberculosis (MDR-TB and XDR-TB) infections which significantly diminish the treatment prospects for patients. This means that there is a distinct need for novel anti-TB drugs with unique targets which will allow them to circumvent the resistance to conventional drugs. One such target is the Galactofuranosyl Transferase 2 (GalfT2) enzyme. This enzyme plays a key role in the generation of the alternating beta-1,5 and beta-1,6 furanose linkages which make up a significant portion of TB’s complex cell wall. Knock-out studies have shown that this enzyme is vital to TB viability making it an attractive drug target. Previous work in the Thomas group identified iminosugars as a weak inhibitor of GalfT2. The aim of this project is to synthesise a library of these iminosugar compounds and explore their efficacy as GalfT2 inhibitors using both whole-cell and enzyme assays. Structural elaboration will be performed, principally driven by in silico drug design which will attempt to improve the inhibitory properties. The hope of the project is to identify novel iminosugar compounds which can act as effective anti-TB compounds.
Axonal miRNAs in the development and function of neuron connectivity: intra-axon and inter-neuronal actions 04 Dec 2017
Brain function depends on the correct formation, maintenance and constant changes of neuronal circuits. Among the multiple signaling pathways regulating these processes, microRNAs have emerged as crucial regulators of gene expression able to control the development and remodeling of neural connections. However, there is still a very limited understanding of their role in axon biology and inter-neuronal communication. Our central hypothesis is that specific miRNAs can be transported to the axon and regulate the development and function of neuronal connectivity via the control of local axonal translation (cis-action) and inter-neuronal (trans-action) mechanisms mediated by release of extracellular vesicles/exosomes. We will test this using a multidisciplinary approach with innovative cellular and molecular techniques based around compartmentalised microfluidic devices for the culture of mouse primary cortical neurons. The characterisation of axonal miRNAs and their capacity for intra- and inter- cellular action could transform our current understanding of the role of miRNAs in the development and function of neuronal networks. The impact of these findings will be many, both at the level of basic neuron connectivity, and in the understanding of neurodegenerative disease, where disruption of axonal projections and neuronal circuits has been intrinsically linked to progressive functional decline.
This research will provide insights into how emotionally salient memories affect behaviour. In tasks where there is no requirement to remember, brain activity measures have shown that previously encountered positive and negative valence material is more likely to be retrieved than neutral material. It is important to extend this research to understand how this kind of involuntary retrieval influences behaviour. Participants will see negatively valenced as well as neutral pictures. In a subsequent task, participants will see these pictures again, interspersed with new (unstudied) pictures. There will be two blocks in this task. In one, participants will indicate whether the pictures are presented to the left/right of fixation. In the other, participants will indicate whether the picture depicts an event occurring indoors or outdoors. In both tasks, the key measure is reaction time. The critical questions are whether: (i) prior exposure increases reaction times, and (ii) this is more likely for negative valence pictures. Using two tasks permits an assessment of whether focusing on perceptual (block one) or semantic content (block two) influences when interference occurs. At issue is the influence that involuntary retrieval of emotional material has on behaviour.
Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy in adults. It is a highly debilitating condition affecting more than 100,000 patients in developed countries with an average life expectancy of 58 years. DM1 is primarily a neuromuscular disorder, which also affects a range of other systems including the heart, brain, endocrine and digestive systems. Patients may also show specific patterns of psychological dysfunction and personality traits, cognitive impairment/mental retardation and excessive daytime sleepiness. All features show an obvious deterioration with time and difficulty swallowing and sucking food into the lungs in the later stages of the disease contribute towards chest infections and represent a major cause of morbidity and mortality. There is no treatment for DM1. DM1 is caused by a repeat expansion mutation in the 3' untranslated region of the DMPK gene. Unaffected people have 5 to 30 copies of this sequence whereas patients may have hundreds or sometimes thousands of copies. When expressed the DMPK expansion transcripts remain in the nucleus where they form distinct spots or foci. Professors Chris Hayes and David Brook at the University of Nottingham developed an assay to screen for compounds that might provide a treatment for DM1. They identified small molecules that target a novel protein and destroy the spots in DM1 cells, thereby leading to a significant reduction in the faulty RNA and other molecular features of the disorder. Their drug discovery approach, in collaboration with Argenta, a Charles River company, is based on targeting this novel protein, by refining the chemical starting points to make them more selective and more suitable for oral administration to patients. The multisystem nature of DM1 provides particular challenges but Professors Hayes and Brook anticipate that a successful drug would target most/all features of the disease
Targeting Cholangiocarcinoma with drugs that regulate epigenetic mechanisms of tumour survival 27 Apr 2017
Cholangiocarcinoma (CCA), a malignant transformation of cholangiocytes, the epithelial cells lining the biliary tract. CCA has a poor prognosis with a high mortality rate as a consequence of a poor understanding of the molecular biology of the cholangiocyte transformation, and a consequent lack of effective drug therapies. CCA progresses with unspecific, invasive and silent symptoms, and is usually diagnosed in the advanced stages. Surgery represents the only curative treatment for CCA and has a high rate of recurrence. Chemotherapy and radiation therapies have been used in an attempt to control this cancer and improve the survival of patients with advanced CCA. However, these therapeutic strategies are not effective in prolonging long-term survival. Inhibiting epigenetic regulation of gene expression has gained momentum as a method of targetting tumours as it can inhibit the expression of multiple oncogenes and repression of multiple tumour suppressor genes at once. Epigenetic inhibitors are in several stages of clinical trails for other cancers however the study of epigenetics in cholangiocarcinoma is limited. The hypothesis of the study is epigenetic inhibitors that are effective at targeting other solid tumours will induce apoptosis and growth arrest, and reduce the expression of oncogenes in cholangiocarcinomas.
Cordycepin is an extract that is purified and isolated from Cordyceps Militaris, a specific strain of caterpillar fungus. It is commonly found in traditional Chinese medicine however my research aims to determine whether the compound may also be implemented in conventional medicines for the treatment of cancers and inflammatory diseases. My supervisor has already established that cordycepin down-regulates gene expression by inhibiting the polyadenylation step involved in the formation of the mRNA transcript. However, I will be investigating the effects of cordycepin on the metabolic activity and the translocation of a particular transcription factor associated with stimulating the expression of inflammatory genes in tissue culture samples containing macrophage-like haemocytes. This will be compared to other fungal extracts of insect-infecting and non-insect infecting origin to identify whether suppression of the anti-inflammatory response is replicated across a range of these compounds. Various analytical techniques will be employed such as MTT assaying and immunohistochemistry. The end results of my study will allow me to conclude how cordycepin affects the immune response and whether certain fungal extracts can be used in new immunosuppressive drugs for the future.
There are many factors that influence cardiac electrophysiology in a particular patient. These include the size and shape of the heart, the orientation of tissue fibres within it, and the electrophysiology of different cells and cell types throughout the myocardium (from endo to epicardium, apex to base, and left to right). These properties are very difficult to measure precisely (or at all), and it is not yet known how uncertainties in these properties affect the predictions that we make for electrical activation and the likelihood of arrhythmias. In this project we will use techniques from weather forecasting to estimate the uncertainty in predictions. Simulations are run repeatedly with different conditions. The spread of the subsequent model predictions increases over time, and allows uncertainty to be estimated for the predictions, and for this to be communicated to the public. We will transfer these techniques to electrophysiology, estimating uncertainty in the factors above, and running multiple tissue simulations to estimate the uncertainty in model predictions, and to visualize this with the results we present. This is a first step to allowing predictions to be used in a clinical setting, when their results could directly impact or decide a patient's treatment.
Stochastic modelling for detecting interactions and evidence of selection between phase variable genes of Campylobacter jejuni 27 Apr 2017
Recently, the laboratories of Dr. Mike Jones (School of Veterinary Medicine and Science, Nottingham) and Dr. Chris Bayliss (Genetics Department, Leicester) generated a large amount of in vivo data collected from two populations of birds at three time points during colonisation of chickens by Campylobacter jejuni. One of the populations was immunised prior to administering Campylobacter jejuni to the birds while the other population was not immunised and serves as a control group. The immunisation was with a whole cell lysate of the bacterium, which elicited C. jejuni-specific serum antibodies but did not prevent colonisation. The observation points include inoculum (which was the same for both groups), one time point during the life of a bird (anal swabs) and a final time point when swabs and post-mortem caecal samples were collected. This project aims to determine how immunisation affects specific patterns of switching in the phase-variable genes of Campylobacter jejuni occurring during host adaptation of this foodborne pathogen. To analyse the data and make qualitative and quantitative conclusions, a variety of statistical techniques will be used in combination with mutation only and mutation-selection models.
The use of equine hepatocytes for the prediction of the pharmacokinetics and potential drug-drug interactions of Meloxicam and the nutraceutical Quercetin 27 Apr 2017
There is limited information available about equine drug metabolism to ensure optimal dosing, decrease risks of drug-drug interactions and to predict the effects of treatments. New findings are particularly important in the horse racing industry and for equine welfare. As there are ethical issues associated with in vivo experimentation, using equine hepatocytes to develop a highly predictable horse in vitro model to estimate the in vivo clearance and potential drug-drug interactions may be a way forward. This would reduce costs and reduce and refine animal testing. More research is needed to understand its benefits and limitations. This project is designed to use fresh and cryopreserved equine hepatocytes to predict the in vivo pharmacokinetics of Meloxicam, commonly used for the treatment of inflammation. This drug will be used as its pharmacokinetic data in the horse is known. Furthermore, potential drug-drug interactions of Meloxicam with Quercetin, a flavanol, used in equine nutraceutical products as an anti-inflammatory will be assessed. The main experimental aims are to compare metabolism (enzyme kinetics) of Meloxicam in fresh and cryopreserved equine hepatocytes and scale results physiologically to estimate hepatic clearance. These results will then be compared with measured pharmacokinetic blood clearance obtained from in vivo pharmacokinetics.
This five-year collaborative programme will develop approaches for understanding laboratory animal research as a nexus, asking how reconceptualising connections and generating communication across different perspectives can contribute to improving the future of animal research. New research will draw attention to historical independencies between science, health and welfare; identify challenges emerging at the interfaces of animal research and create opportunities for informing policy and public engagement. We suggest collaborative approaches are essential for understanding how rapid transformations across science and society are changing the patterns of responsibility, trust and care which hold together, or constitute, this nexus. We will deliver new: integrated research across the social sciences and humanities, using historical research to inform understanding of present challenges and create new engagement opportunities for the future; interactive research projects, co-produced with researchers, animal suppliers, veterinarians, publics and patients, to investigate the contemporary dynamics of animal research; interfaces for generating cultures of communication with publics, policy-makers and practitioners across the animal research nexus. This programme brings together five leading researchers on the social and historical dimensions of animal research, uniting the strengths of five institutions, engaging creative practitioners, and advancing the work of five early career researchers and three PhD students.
In the UK an estimated 620,000 people suffer from inflammatory bowel disease (IBD). Poor access to primary tissue and a lack of animal models that faithfully reproduce the human condition has left us with an inadequate understanding of how to diagnose and treat IBD. These issues are exemplified by Crohn’s disease (CD), a debilitating disease where chronic inflammation leads to intestinal perforation that requires surgical removal. Here we propose to apply our recently published intestinal culture platform to model CD to address 2 interlinked objectives: 1) Generate an in-vitro intestinal enteroid model of Crohn’s disease. There are currently no reliable in-vitro models of CD. To create a new model of CD we will generate "mini-intestines" using intestinal biopsy from patients with CD. 2) Create a platform to study microbiota dysbiosis. Changes in the types of bacteria in the intestine is believed to be important in the initiation and progression of CD, however this has not been well studied. Here we will validate a bacterial injection platform into CD enteroids that can be used for future studies on microbiota dysbiosis.
Structure-aided discovery of kinase inhibitors as targeted therapeutic agents for breast cancer 30 Jul 2016
Kinases are important targets for blocking cancer progression. However, many remain to be exploited. For example, no drugs are yet available to specifically inhibit any kinase which is switched on by a regulatory protein called calmodulin. Nonetheless, faulty expression of these “CaMK” enzymes is now thought to play a key role in breast cancer progression. The Wellcome Trust has funded the CAMSEED consortium to discover small molecule inhibitors for a CaMK protein involved in basal-like breast cancer. The three dimensional structure of this target has been solved by the Structural Genomics Consortium and Professor Stefan Knapp at the University of Oxford. Interactions with small molecules are being screened by Professor Michael Overduin’s lab at the University of Birmingham using superconducting magnets and high throughput robots at the national HWB-NMR facility. The design of improved inhibitors that can enter cells and selectively block the oncogenic state is being led by Professor Peter Fischer at the University of Nottingham, with Colin Kenyon at CSIR, Pretoria, designing deuterated analogs for enhanced activity. The result of the two year project is expected to be a set of lead molecules for development as potential therapeutic agents for breast cancer, and may yield a new approach for using nature’s own inhibitory mechanisms to block cancer-causing kinases.
Achieving controlled human pluripotent stem cell derivation and expansion using Inter-alpha-Inhibitor with a novel polymer substrate 19 Apr 2016
This project will combine the latest advances in synthetic surfaces with the breakthrough discovery of Inter-alpha-Inhibitor (IalphaI) as a soluble, cell attachment-inducing protein, to provide a simplified and economical culture method for human pluripotent stem cells (hPSCs). The current gold standard for hPSC maintenance in vitro still requires ill-defined components with batch-to-batch variability, such as albumin or matrigel. While these conditions have now been refined to purified recombinant components, their high cost still prohibits the large-scale expansion schemes required for therapies. Synthetic surfaces overcome this problem, they are easy and inexpensive to mass-produce, and most important, their production is flexible enough to easily accommodate variable formats depending on the project requirements. Some synthetic surfaces have already been shown to support human PSC growth and expansion, but they still require high concentrations of albumin and underperform compared to traditional methods. I aim to design a hPSC culture method combining a defined, albumin-free medium with a synthetic surface, describe its biological implications on independent hPSC lines and then translate this method to 3D microcarriers and bioreactor-based large-scale expansion. This project will pave the way to clinically safe hPSC lines and scalable culture conditions to make large-scale stem cell therapy a reality.
Investigating molecular mechanisms underlying lymphovascular invasion in invasive breast carcinoma. 01 Apr 2016
Lymphovascular invasion (LVI) refers to the presence of Invasive Breast Carcinoma (IBC) cells within the lymphatic spaces. LVI is highly associated with poor prognosis and higher rates of recurrence and mortality. This biological phenomenon is regulated through multistep molecular mechanisms that will lead eventually to distant metastasis. Previously, it has been explained how IBC cells are capable to breakdown the surrounding stroma and transmigrate through vessels' lamina. However, the selective tropism of IBC cells toward the lymphatic vessels is not clear. The biochemical and biological molecules that construct the conditions of tumour microenvironment of invasion-metastasis cascade would be recruited by IBC cells through a genetic regulated cell to cell, or cell to stroma signalling pathways. In previous study, IBC cases have been characterised and grouped according to their LVI status, and in-depth genomic/transcriptomic profiling analysis has revealed sets of genes that are significantly associated with positive LVI cases. Those differentially expressed driver genes of LVI would be our genes in query to investigate their role as potential prognostic and therapeutic targets. The molecular mechanisms that regulate LVI in IBC may be decoded by applying immunohistochemistry techniques on human IBC tissues, and analyse the findings with the correspondent clinicopathological data.
The role of exercise and the NAD-biosynthetic enzyme NMNAT1 in the browning of white fat 01 Apr 2016
The current rise in consumption of high fat diets and sedentary lifestyles has precipitated a step-like increase in the incidence of obesity and type II diabetes. The role of most of the adipose tissue in the adult is to store fat. However activation of a specialized type of adipose tissue, brown fat, can suppress weight gain and improve metabolic syndrome. A third type of adipocytes are beige cells, which are inducible "brown like" adipocytes that develop within the white fat in response to increase to exercise. Recent evidence indicates that over-expression of Sirt1 results in an increase of beige cells. Sirt1 requires NAD for activation. In the cell nucleus, NAD is synthesised by the enzyme NMNAT1. Here we propose to study the protein expression of the beige adipocyte marker UCP-1 in the white fat of NMNTA1-tg mice, NMNAT1-KO mice, wild type sedentary or wild type mice that exercised for 4 weeks. We hypothesize that exercise or increase in NMNAT1 expression (NMNAT1-tg) will lead to an increase of beige cells in the WAT, due to proliferation of new cells. The opposite will happen when NMNAT1 is partially knocked down.