- Total grants
- Total funders
- Total recipients
- Earliest award date
- 02 Jan 2018
- Latest award date
- 21 Dec 2018
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
Community Litter Pick Fundraising 19 Jun 2018
Organiz ing different area clean up around the Lostock area. Getting the community involved in "Loving where they live!" Encouraging young people to get involved in their community using establish links to college and Junior schools in the area.
Kids play activities 25 Jul 2018
would like to introduce kids play activities in the park and would also like to make full use of the current redundant bowling green currently located in Lostock park by creating a bowling club for the younger generation and encourage them to go outdoors and get involved with the community as well as make full use of the outdoor equipment.
Nanomagnetism in cancer treatment: How Iron Oxide Nanoparticles can be used to target therapies to the brain 31 May 2018
Iron Oxide Nanoparticles (IONPS) are a class of nanoparticles used in targeting therapies towards tumour sites. The emerging field of nanotechnology has garnered a lot of interest in tumour therapy especially for brain tumours. IONPS can be coupled with an anticancer drug and with the use of magnetic field (Muthana et al., 2015) can be ‘steered’ towards a desired site within the body. This technology would hope to increase the amount of drug concentration to the tumour site which also means that the amount of drug delivered systemically could be reduced. In this project, the student will learn how to use FEMM (Finite Element Mathematical Modelling) to create magnetic array (a special arrangement of magnets) to optimise the magnetic field strength. This will be tested through a range of in-vitro experiments for its efficacy. Laboratory training will include isolating human peripheral mononuclear cells (PBMCs), flow cytometry to examine PBMCs cell viability/cell death following the addition varying concentrations of IONPS. Data analysis will involve using a software called FlowJo (used for flow cytometry) and Prism software to carry out statistical analysis. The student will be able to learn how to operate a confocal microscope, carry out immunohistochemistry and processing tissue samples.
Surgery and chemotherapy, which preferentially kills dividing cells, are the main treatments for colon cancer: a common disease in the developed world. To develop better treatments requires defining the molecular events that cause tumours to grow so that these specific aberrations can be bypassed. Mutations in a gene called Adenomatous polyposis coli (Apc) are the most common molecular change identified in colon tumours. The Näthke lab recently discovered that APC protein (encoded by the Apc gene) binds to and regulates the abundance of another protein (MINK1) with roles in cell division and movement. This raises the possibility that faulty control of MINK1 by mutated APC could explain why cells in colon tumours divide excessively and migrate aberrantly. I will investigate the function and control of MINK1. Using cells grown in dishes and also cells that form mini-gut structures called organoids, experiments will be designed to determine whether and how MINK1 is required for Apc mutations to cause cancer, and how MINK1 affects the structure of the gut lining. These issues will also be addressed in mice whose guts lack the Mink1 gene. Results will help to decide whether human colon cancer can be treated by new drugs that target MINK1.
Nonsense mediated decay (NMD) is a quality control mechanism used by eukaryotic cells to destroy messenger RNAs containing incorrectly positioned translation termination codons . NMD, in combination with alternative RNA splicing (AS), also provides a potent mechanism for natural changes in gene expression in developing brain [2-5]. The main goal of my summer project will be to test the hypothesis that progressive down-regulation of an RNA-binding protein called PTBP1 during mammalian neurogenesis promotes neuronal identity by changing AS patterns and triggering NMD of multiple neural precursor-specific transcripts. I will first follow up on the RNA sequencing screen carried out in the Makeyev lab and validate bioinformatically predicted AS-NMD targets using Reverse Transcription PCR and quantitative PCR analyses of developing nervous system samples and embryonic stem cells undergoing neuronal differentiation in vitro. I will then analyse AS-MND regulation for one example showing the most robust regulation. This will be achieved by designing minigene and CRISPR-Cas constructs specific for AS-NMD promoting exons and testing these reagents in mouse ES cells undergoing neuronal differentiation or treated with siRNA against PTBP1. The results of this work should improve our understanding of the AS-NMD pathway and evaluate its contribution to neuronal differentiation.
The concept of cellular brain repair for Parkinson's disease is relatively simple - if brain cells die in this condition, then it should be possible to replace these cells through transplantation of healthy cells back into the brain. Over the past three decades, numerous animal studies and several clinical trials in human patients have shown that this concept has significant potential for repairing the brain affected by Parkinson's disease. However, poor survival of the healthy cells has limited the widespread roll-out of this cellular reparative approach to patients. Biomaterials, that is, materials that have been engineered to interact safety with living tissue for therapeutic purposes, have the potential to improve such cellular reparative therapies for Parkinson's disease. Specifically, injectable biomaterials gels have the potential to significantly improve cell survival by providing a physical scaffold and pro-survival environment for the implanted cells. Thus the aim of this proposal is to determine if biomaterial hydrogels can be used to improve cellular reparative therapies for Parkinson’s disease using animal models of the condition. We will specifically investigate the beneficial effect of biomaterials on stem cell-derived neuron cell transplantation approaches.
Neurotrophins and their receptors play a key role in the maintenance and remodelling of the nervous system, and defects in trophic signalling are associated with mental illness as well as neurodegeneration. To date, the cellular mechanisms regulating neurotrophin receptor bioavailability are not fully understood. Here we focus on BDNF and its receptor, TrkB, which are widely expressed throughout the central nervous system. This project will investigate the role of two novel potential TrkB regulators that recently emerged from our screens. Candidates will be expressed in HEK-TrkB cells and primary cortical mouse neurons, and (i) TrkB receptor expression levels and (ii) downstream signalling events will be investigated using both Western blotting and immunofluorescence techniques. These experiments will address whether the candidates modulate TrkB availability and activity. A better understanding of the cellular mechanisms underlying TrkB regulation may highlight potential therapeutic targets to counteract TrkB degradation and restore sensitivity of vulnerable cells to the beneficial actions of BDNF.
The aim of this project is to investigate whether specific metabolites produced in the duodenum during digestion and correlated with the release of the gastrointestinal hormone glucagon-like peptide-1 (GLP-1) actually drive this release of GLP-1 to regulate energy and glucose homeostasis. We will use gut organoids as a model of enteroendocrine cell function to study the effects of the metabolites tyrosine, taurine and acetone, alone and in combination, and with or without glucose present. Hypothesis: Tyrosine, taurine and acetone will stimulate GLP-1 release from duodenal organoids Aim: To investigate the effects of tyrosine, taurine and acetone on GLP-1 release Objective: To establish whether tyrosine, taurine and acetone alone or in combination with each other or glucose stimulate GLP-1 release from duodenal organoids This work will establish the possible role of these metabolites in driving GLP-1 release, and thus whether using them as dietary supplements may represent a potential therapeutic approach to obesity and metabolic disease.
PhD Grant Proposal 30 Sep 2018
Older people are often classed as either experiencing ‘normal’ cognitive ageing, or ‘pathological’ cognitive ageing as a result of diseases such as Alzheimer’s (AD). However, these classifications fail to reflect the spectrum of cognitive decline that is experienced as we age. Age-related cognitive decline is a hugely important health problem; it has a profound impact on quality of life, increases the risk of depression and may herald dementia. Because of this, it is important to investigate what influences how well we age cognitively. Age itself is the biggest risk factor for cognitive decline. The comprehensive causes and mechanisms of ageing are not fully understood but we do know that the process is closely integrated with inflammation – the body’s immune response to injury or irritants. Although recently receiving significant attention, the precise cause-and-effect relationship between inflammation and cognitive ageing has not yet been fully explored. Using different techniques, this project will investigate the role of inflammation in cognitive ageing, and whether the process can explain why some people are more resilient than others. Understanding the differences in individual’s cognitive decline is critical to developing interventions to prolong cognitive health and to gain insight into diseases of cognition such as AD.
Haemocyanins are oxygen-carrying proteins found in the haemolymph of molluscs and gastropods. They are of interest to biotech and medical research as strongly immunogenic carrier proteins, for making antibodies to conjugated peptides and for use as cancer vaccines. In addition, direct application of haemocyanin to tumours has been shown to produce an anticancer effect, and haemocyanins from several species including keyhole limpet have shown promise in the treatment of bladder cancer, colon cancer and melanoma. Particularly striking are their lack of toxicity and adverse effects. Recently, Mikota PLC have developed protocols for the purification of a new haemocyanin, Biocyanin SLH, from the slipper limpet Crepidula fornicata. The main aim of our proposal is to test the potential of Biocyanin SLH as an anticancer agent, by incubating it with a panel of cancer cell lines and assessing its ability to induce cell death. In addition, we will investigate the signalling pathways involved in the anticancer action of Biocyanin SLH, determining whether cell death occurs via apoptosis or necrosis, and analysing cellular production of stress molecules. Finally, we will label Biocyanin SLH with a fluorescent dye to track its interaction with cells using confocal microscopy. Keywords: haemocyanin, cancer, cell death.
Developmental gene expression profiling for novel mediators of epithelial fusion in the chick embryo 31 May 2018
Title: Developmental gene expression profiling for novel mediators of epithelial fusion in the chick embryo. Hypothesis: Tissue fusion processes in vertebrates are essential for normal embryonic development. Novel factors recently identified in our lab using transcriptome profiling during epithelial fusion within the embryonic chick eye may have roles in fusion in additional embryonic contexts. We will perform whole mount in situ hybridization for the genes NTN1, FLRT3, CYP1B1 and RGMB using chicken embryos at key fusion stages in the developing neural tube, body wall and heart. These analyses will inform us whether the protein products of these genes are required for fusion in these tissues. Uniquely in the chicken embryo, the palatal shelves do not fuse. Therefore, identification of continual gene expression in the developing non-fusing palate will also help to identify which of these factors may act to prevent fusion. Data will be collected and analysed using brightfield microscopy and optical projection tomography (OPT). Key goals: (i) Establish spatial gene expression profiles for four genes between chick embryonic stages HH16-26; (ii) determine those genes with conserved roles in fusion for multiple tissues; (iii) categorize genes into likelihood of promotion or inhibition of tissue fusion.
Emerging evidence suggest that systemic infection can accelerate the onset and/or progression of cognitive decline in Alzheimer’s disease, but the underlying biological mechanism remain unknown. Exposure of AD mouse models to a real systemic infection results in exaggerated neuroinflammation and AD-like pathology and preliminary microarray analysis suggest this may be due to increased levels of type I or II interferon and/or it’s down-stream signalling pathways. Interferons are produced in response to viral and bacterial infections and well known to be associated with mood changes and depression. In this project we will test if these pro-inflammatory cytokines also play a role in progressing AD-like pathology. Brain tissue from AD mice exposed to a systemic bacterial infection has already been collected, with a control group treated with saline. The expression levels of interferons and their signalling pathways will be explored in this archived tissue and in primary neuronal cultures expressing human Tau. The in vitro cultures will allow us to test if exposure to interferon promotes spreading of tau pathology and if inhibition of the signalling pathways prevents progression of AD-like pathology. This could later be applied to in vivo AD disease models, taking into consideration behavioural changes.
Exploring endosomal signalling of G protein coupled receptors (GPCRs) using luciferase complementation and luminosensing optogenetics 31 May 2018
Recently G protein coupled receptors (GPCRs) have been shown to signal from intracellular compartments such as endosomes, as well as the cell surface. There is increasing evidence that some synthetic drugs can activate such intracellular located GPCRs directly, but the functional consequences of this activation have been difficult to isolate. This project will study endosomal signalling from engineered optogenetic receptors (OptoXRs), activated by light and coupled to the Gq pathway linked to calcium mobilisation. I will deliver the light stimulus to OptoXR using bioluminescence from a luciferase enzyme, in a local manner to receptors either at the cell surface or within endosomes. This will be achieved using a complementation system, in which luciferase fragments are tagged to the OptoXR and cell surface or early endosomal markers respectively. Active luciferase will therefore only be reconstituted to deliver the light when the OptoXR is present in the same location as the expressed marker. I will then be able to compare the effect of adding the substrate on OptoXR calcium responses in which case, to determine whether calcium signals are produced from receptors in different locations. This will be backed up by confocal and luminescence microscopy to identify reeptor and luciferase locations.
Investigating the relationship between the cerebellum and cognition in both health and disease 30 Sep 2018
The cerebellum is traditionally ascribed only a role in motor coordination. With it containing more neurones than the rest of the central nervous system combined and with connections with almost every other area of the brain concerned with cognition, this seems exceptionally unlikely. Indeed, studies utilising magnetic resonance imaging (MRI) increasingly show strong cerebellar activity associated with cognitive processes. This is still a greatly understudied area with only a few groups researching this. We, therefore, wish to investigate the role of the cerebellum in cognition using large imaging datasets, our own high-field imaging capabilities at Cardiff and various cerebellar-specific MRI processing tools which have not yet been applied to this question. This will allow us to see how well peoples’ cognitive performance in various domains correlates with cerebellar activity and structural differences. Additionally, recent evidence suggests cerebellar structural differences in schizophrenic patients. We wish, therefore, to also investigate if schizophrenia diagnosis and genetic risk for schizophrenia similarly alters cerebellar structure and, if so, at what time during development, if certain cognitive domains are particularly affected and if cerebellar metabolite levels differ in schizophrenic patients compared to non-schizophrenic controls.
Investigating acetylation control of MutSbeta protein (Msh2-Msh3) in DNA triplet repeat expansions. 31 May 2018
Huntington’s disease (HD) is a debilitating, relentlessly fatal neurodegenerative disease. HD is caused by inheritance of an expanded CAG repeat tract in the HTT gene. The CAG repeat continues expanding in the brain of HD patients, and these somatic expansions contribute to disease progression and age of onset. It is known from model systems that the DNA repair protein MutSbeta (Msh2-Msh3 complex) is essential to drive expansions, as knockout of either Msh2 or Msh3 blocks nearly all expansions. Recent work from the supervisor’s laboratory suggests that MutSbeta expansion activity is regulated by post-translational acetylation. This link to protein acetylation is noteworthy with regard to potential therapy, in light of the supervisor’s recent demonstration that inhibiting histone deacetylase 3 in HD mice blocked disease onset. Using cultured human cells, I will test potential acetylation control of the Msh2 subunit of MutSbeta by mutating a putative acetylation site, lysine 73, to convert it to the non-acetylatable arginine (Msh2K73R). I will then test Msh2K73R protein expression and its ability to form MutSbeta complex. I will assist in genetic assays to measure CAG repeat expansions in cells expressing Msh2K73R, compared to wild type. My prediction is Msh2K73R will drive expansions in an acetylation-independent manner.
Investigation into the role of RBM8A/Y14 in the development and function of megakaryocytes and platelets using a human pluripotent stem cell model of haematopoiesis 30 Sep 2018
Platelets are small blood cells, which cause blood to clot, preventing bleeding after injury. They are produced by megakaryocytes, large cells in the bone marrow. In people with low platelet counts (thrombocytopenia), life-threatening bleeding occurs spontaneously or after injury. Studying platelet and megakaryocyte development and function is important in understanding a) diseases causing thrombocytopenia, such as genetic disorders and other conditions, particularly cancer (and chemotherapy) and b) strokes and heart attacks, where platelets are excessively activated, forming clots that block vessels. Using stem cells (special cells capable of becoming any cell type) derived from adult skin or blood samples we grow & study megakaryocytes and platelets in the laboratory. We study a rare genetic disease, Thrombocytopenia with Absent Radii (TAR) syndrome, in which babies are born with very few platelets and abnormal bone formation (particularly the radius in the forearm). Our group discovered the cause of TAR, due to abnormalities in a gene called RBM8A, which helps cells control what proteins are produced; however precisely why this causes TAR is unclear. We believe our research will uncover the mechanism of this condition, helping to treat patients with TAR and improve wider understanding of how megakaryocytes & platelets develop and function.
DNA-clustering in yeast 31 May 2018
We propose to describe mathematically the processes by which telomeres form clusters in the nuclei of yeast cells. It is thought that this is due to the presence of proteins which bind to the telomeres. We wish to investigate the processes which determine cluster size through: 1. forming a mathematical model of the attachment processes through which proteins bind to telomeres. This may involve a site exclusion process, whereby the protein binding rate slows due to the declining number of vacant protein binding sites as the telomere `fills up'; 2. constructing a mathematical model of the aggregation of telomere-protein complexes into clusters, and determine which rate parameters are key to controlling cluster size; 3. investigating the rate of equilibration of these processes. The models we construct will have the form of systems of coupled ordinary differential equations. Through a judicious choice of rate constants, explicit equilibrium solutions will be obtainable, allowing available data to be fitted. Numerical simulations of the process will also be performed, to verify that the equilibrium solutions are accessible within biologically realistic time periods.
Correlating smooth pursuit eye movement with cognitive and behavioural deficits associated with schizotypy 31 May 2018
Deficits in smooth pursuit eye movements (SPEM) reflect the most heritable endophenotype (behavioural manifestation of the underlying genetics linked to diseases pathology) of schizophrenia. In SPEM tasks, participants are instructed to follow a moving target with their eyes. Deficits in SPEM associated with schizophrenia (undershooting and poor initiation) are likely to be caused by an inability to accurately utilise incoming information about the target. These deficits correlate with symptom severity and with trait schizotypy. However, it is unclear how such an endophenotype relates to symptomology. Even when highlighting a link between the endophenotype and cognitive deficits, it remains unclear whether the endophenotype does relate to the entire symptomology of schizotypy or a cluster of symptoms. To address this question, we will correlate SPEM performance with a battery of well-established cognitive tests (measuring inhibition, attention, and working memory) as has been done with other endophenotypes. Furthermore, we will correlate SPEM performance and cognitive deficits with different subscales of schizotypy to establish whether SPEM is related to the global construct of schizotypy or specific clusters of symptoms.
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.