- Total grants
- Total funders
- Total recipients
- Earliest award date
- 03 Jan 2017
- Latest award date
- 21 Dec 2017
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
New Danage Target Wall 13 Mar 2017
Funding under Sport England's Community Asset Fund funding programme for a Capital project titled 'New Danage Target Wall'. This project lists its main activity as Archery. This funding has contributed towards a Archery Range - Archery Range (Indoor)
New Year 9 Cup competition 23 May 2017
Funding under Sport England's Small Grants funding programme for a Revenue project titled 'New Year 9 Cup competition'. This project is a Association Football project, with a focus on younger beneficiaries.
microRNAs in Oscillatory gene networks 31 Jan 2017
MicroRNAs are key regulators of gene function that have emerged as highly represented connectors within gene networks. Current work in the field suggests that microRNAs primarily serve a role in the buffering and regulation of transcriptional and translational network motifs. Unpublished data suggests that microRNAs are found in certain network motifs, such as double feedback loops, more frequently than would be expected by chance. Dynamic gene expression is a field which has recently been shown to be important in the understanding of progenitor cell maintenance and differentiation. Modulation of dynamic gene networks by microRNAs has been shown to be able to control the timing of progenitor cell differentiation in neuronal progenitor cells. It is not currently understood how microRNAs integrate into oscillatory gene networks or if they perform similar regulatory roles in other oscillatory network motifs. Using a top down computational approach gene interaction maps will be generated for human transcription factors and microRNA target predictions. Utilizing this map potentially oscillatory gene network motifs will be identified and their interactions with microRNAs predicted. A subset of neuronal transcription factors which are found within potentially oscillatory network motifs will be selected, validated and the functional analysis of the microRNA interaction investigated.
Using data collected from a prospective clinical cohort of people with head and neck cancer (HNC)-Head and Neck 5000 (H&N5000), I will examine the potential value of baseline (pre-treatment) biological, clinical and lifestyle factors in predicting HNC prognosis at one year and three years post diagnosis. I will look at the association between tobacco and alcohol consumption and measures of outcome- overall survival, disease-free survival, metastasis, and second primary tumour (SPT) development. I will investigate whether behavioural change i.e. abstaining from, or reducing the consumption of alcohol and tobacco improves clinical and self-reported health outcomes in this population. To better understand how smoking and drinking behaviours may be influencing prognosis, I will analyse the methylation and metabolite profiles of baseline blood samples. I will explore whether there is an association between DNA methylation and metabolite levels and tobacco and alcohol consumption. Should I identify sites that are differentially methylated in smokers and drinkers, or metabolites that vary by smoking/drinking intake, I will evaluate whether they could potentially act as biomarkers for cancer progression and survival. I will look to develop a risk score that incorporates clinical, biological and lifestyle risk factors, which could be developed for use in clinical decision-making.
Probing the role of outer membrane transport processes in host-pathogen interactions using computational and single-molecule biophysical approaches. 31 Jan 2017
The outer membrane (OM) of Gram-negative bacteria is a significant protective barrier. It is composed of an inner leaflet of phospholipids and an outer of lipopolysaccharide (LPS) with OM proteins (OMPs) that span the membrane. Recently OMPs have been shown to be inserted at discrete and non-uniform locations across the membrane, where they remain due to restricted lateral diffusion. These ‘islands’ are pushed to the poles by cell growth, with new material inserted at mid-cell. OM turnover during bacterial growth may have a role in immune system evasion. One key mechanism regulating human immune responses is the assembly of complement components on the OM nucleated by immunoglobulin binding. This process can lead to lysis of bacteria through insertion of pore complexes in the OM. Complex formation depends on localised clustering of antibodies, which is constrained by the location and molecular diffusion of antigens in the OM. In this project we will use computational and single-cell biophysical techniques to test our hypothesis that spatial confinement of LPS and OMPs near their insertion sites influences activation of the antibody-mediated complement pathway. We will test our hypothesis in Escherichia coli and Salmonella typhimurium, where immune evasion has a key role in pathogenesis.
HIV prevention among young women in eastern Zimbabwe: Developing HIV prevention cascades and interventions to improve uptake and adherence 31 Jan 2017
In southern Africa, nearly 30% of new HIV infection occur among young women (15-24). While treatment as prevention may have impacts on HIV transmission, the implementation of efficacious HIV prevention interventions is critical for achieving the goal of ending the AIDS epidemic by 2030. Analogous to HIV treatment cascades, HIV prevention cascades (HPCs) have the potential to support the evaluation and implementation of HIV prevention efforts. However, there is a lack of scientifically robust methods to measure and interpret HPCs. Similarly, behavioural economic theory has been shown to provide fruitful insights for improving ART uptake and adherence but its application to HIV prevention is limited. Focusing on HIV prevention among young women (15-24), this projects aims at filling these gaps in HIV prevention research. The objectives are: Develop multi-level theoretical frameworks of factors influencing HIV prevention uptake and adherence among young women. Define each step of HPCs in relation to HIV prevention among young women and develop questions for measuring these. Develop questions for interpreting these HPCs. Test these methods in a high HIV prevalence sub-Saharan African setting. Develop interventions to improve HIV prevention uptake and adherence based on behavioural economic theory.
Ras proteins are molecular switches that regulate signalling pathways involved in cell proliferation and survival. These form transient nanoclusters on the plasma membrane, whereby Ras effectors are recruited. The spatiotemporal organisation of lipids within the Ras nanoclusters determine Ras function in signal transduction. Incorporation of dietary fats such as omega 3 polyunsaturated fatty acids (n3-PUFA) into the membrane phospholipid bilayer alters their biophysical properties. In addition, n3-PUFA has been associated with cancer prevention and attenuation of Ras signalling. We propose that n3-PUFA modulation of Ras nanoclustering is responsible for the attenuated signalling response. Different Ras isoforms occupy distinct nanoclusters. In addition, both isoform and oncogenic mutation-specific Ras signalling differ. It is unclear whether the role of n3-PUFA is highly context specific or if they are pan-Ras modulators. Therefore, to test our hypothesis and determine the specificity of n3-PUFA effects, we will profile the proteome microenvironment of different Ras isoforms and mutation variants treated +/- n3-PUFA. In parallel, studies measuring the nanoclustering responses of the same Ras variants to n3-PUFA will also be performed. These results will be correlated with studies profiling the signalling network response. Together, these studies will define the extent to which n3-PUFA modulates oncogenic Ras signalling.
Dysregulation of the transcription factor nuclear factor-erythroid 2 p45-related factor 2 (NRF2) has been observed in many malignancies, and has been linked to both chemo and radio resistance. While the fundamental aspects of NRF2 regulation are relatively well-established, the mechanisms whereby NRF2 target genes are conditionally expressed under basal, de-repressed, or pathological conditions remain unclear. This severely limits the development of effective therapeutic strategies that target the NRF2 pathway. Therefore, this project aims to define conditional NRF2 target gene profiles and investigate the driving mechanisms behind the differential regulation of these genes. Initially a bioinformatics approach will be used to investigate differential NRF2 target gene profiles in a range of cancer-derived cell lines with non-physiological levels of NRF2. Subsequently, a subset of the cancer-derived cell lines identified from the bioinformatics screen will be subject to genetic manipulation to generate models of basal or de-repressed NRF2. Finally, comparative omic profiling of these models will be performed to identify the regulatory networks that give rise to differential expression of these NRF2 target genes. This data will be correlated with comparative proliferation and drug sensitivity profiles to provide new insight into pathophysiological mechanisms that drive cancers progression and drug resistance.
KIFC1 (HSET) is a minus-end-directed kinesin whose depletion promotes multipolar mitosis in cancer cells carrying additional centrosomes. Centrosome amplification often occurs in breast and ovarian cancers where KIFC1 is also frequently overexpressed. While cancer cells usually overcome the presence of additional centrosomes by clustering them into two groups to form pseudo-bipolar spindles, they lose this ability in the absence of KIFC1. As multipolar mitosis is usually lethal, targeting KIFC1 may selectively kill cancer cells without affecting non-transformed cells. This exciting hypothesis currently lacks systematic validation. Here, the KIFC1 requirement for normal mitosis and survival will be addressed in a panel of cancer and non-transformed cell lines. Stability of proteins in cells may be regulated by a family of ~90 deubiquitylase (DUB) enzymes, which recently aroused interest as potential drug targets. Targeting a DUB that stabilizes KIFC1 would be predicted to promote KIFC1 degradation and multipolar mitosis. In this project we will identify DUBs that maintain cellular levels of KIFC1, then characterize the effect of their depletion and their mechanistic interaction with KIFC1. Lastly, we will assess the clinical relevance of our findings, by evaluating expression of KIFC1 and its regulatory DUBs in breast cancer patient tissues and performing clinicopathological correlations.
Background: The risk for many common complex diseases, including type 2 diabetes, increases with age. Technological advances have recently enabled large-scale investigation of genomic markers of ageing in population-based studies. Whether genomic ageing contributes to the age-related rise of diabetes and related metabolic disorders is unknown. Aim: To systematically identify and study genomic markers of ageing, including telomere length, DNA methylation, and chromosome loss, and investigate their causal roles for morbidity and mortality from type 2 diabetes and other common complex diseases. My overall aim will be achieved by addressing the following specific objectives: Objectives: 1. To perform a systematic literature review of genomic markers of ageing to identify determinants and consequences and assess methods for their characterisation in epidemiological studies. 2. To identify and characterise genetic and modifiable behavioural and environmental risk factors of genomic ageing in large-scale population-based studies. 3. To investigate causal roles of genomic markers of ageing for morbidity and mortality from ageing-related diseases using Mendelian randomization methods, and conduct exploratory studies of the underlying pathways through detailed metabolomic characterisation.
Investigating the regulation and function of gap and Hox genes during segmentation in a short germ insect 31 Jan 2017
Three of the most abundant and diverse animal phyla - the Arthropoda, Annelida, and Chordata - are segmented along their anterior-posterior axis. Embryos of the fruit fly Drosophila form all of their segments simultaneously. In contrast, most arthropods, and all vertebrates and annelids, produce the majority of their segments sequentially. Although the molecular and genetic mechanisms regulating simultaneous segmentation have been well-characterised, our understanding of the mechanisms regulating sequential segmentation, especially in arthropods, remains poor. Gap genes are among the best-characterised components of the segmentation cascade in Drosophila. They are also expressed during segmentation of sequentially-segmenting arthropods. In Drosophila, gap genes define broad regions of the embryo; however, in sequentially-segmenting arthropods, they appear to have a different role, possibly mediated via Hox genes. Determining their function in sequential segmentation may shed light on how this developmental process is regulated, and how it was modified to give rise to simultaneous segmentation. For my PhD, I therefore propose to investigate the expression patterns, interactions and functions of gap and Hox genes in a simultaneously-segmenting arthropod, Tribolium castaneum. To accomplish these goals, I will analyse gene expression, cell behaviours and embryonic development in wild type and genetically manipulated Tribolium embryos.
This PhD focuses on developing statistical methods to discover gene – environment (G-E) interactions. To date there has been some interest in testing for G-E interactions in animal models, but limited success in uncovering examples of G-E interactions in humans. This is in part due to the problem of exposure assessment, or rather, because representative data on the environment of a number of individuals over a lifetime has been hard to acquire. However the data recently made available by the UK BioBank, on over 500000 individuals and a wide array of environmental covariates, may now make it possible to detect these interactions. We aim to use a Bayesian methodology to first test a number of known models, such as a random effects model, against the dataset. We will then attempt to use a Gaussian Process Regression model to identify covariates involved in G-E interactions. This approach is advantageous as GPR is non-parametric, thus avoiding the curse of dimensionality, and places no assumptions on the order of interactions. However as this method currently scales in a cubic manner following the number of samples, significant computational challenges remain.
Genome wide association studies demonstrate that amyotrophic lateral sclerosis (ALS) has a large genetic contribution and a gender bias in risk. However, these studies also indicate that we still have much to learn about the genetic causes of ALS. To explain this missing component we hypothesise that endogenous non-LTR retrotransposons, which are known to be active in the human genome, result in novel insertions that can act as germline predisposition variants or new de novo mutations. These non-LTR retrotransposons include LINE-1, Alu- and SINE-VNTR-Alu (SVA) elements. We are currently identifying novel somatic insertions in DNA from both motor neurons and lymphocytes of individuals who have died of ALS using a technique termed retrotransposon capture sequencing. This data is now available to validate, data-mine and address the functional consequences of such insertions. Particular focus will be given to insertions on the X chromosome which might in part explain the gender bias. The proposal is therefore to determine if: a) Increased or novel retrotransposition events have occurred in the motor neurons of individuals with ALS which would correlate with neurodegeneration of these neurons. b) Specific germline insertions are a predisposing factor for ALS.
The metazoan Hsp70 disaggregase system is the only known human protein complex capable of resolubilising aggregated protein, conferring a protective phenotype for a range of pathologies. Disaggregation occurs through the dynamic assembly of a Hsp70/110 complex, initiated by J-protein recruitment of substrate. The structure of the active complex is currently unknown, as is the mechanism of disaggregation. This project will employ an interdisciplinary approach to structurally characterise the disaggregation of alpha-synuclein amyloid fibres in vitro by the human proteins DNAJB1 (J-protein), Hsc70 (Hsp70) and Apg2 (Hsp110). There will be a primary focus on understanding two particular elements of disaggregation. Firstly, how do J-proteins recruit substrate to activate disaggregation? This will be investigated using electron tomography, taking advantage of the recent "resolution revolution" in the electron microscopy field. Secondly, what is the mechanism of the active disaggregase complex as it is resolubilising aggregates? To answer this, we aim to track individual alpha-synuclein fibres by atomic force microscopy and total internal reflection fluorescence microscopy as they are solubilised during disaggregation. Given the role of aggregation in a broad range of debilitating diseases, increasing the understanding of disaggregation in humans has the potential to eventually lead to significant public health benefits.
Histones are some of the most well-conserved proteins between eukaryotic species and specific post-translational histone modifications often trigger the same cellular responses in different organisms. However, the histones of Trypanosoma brucei, the causative agent of sleeping sickness, are more divergent than the histones in other organisms. In most eukaryotes, heterochromatin is formed by adding methyl groups to Lys9 of histone H3. Trypanosomes lack the H3K9 residue and heterochromatin formation in these parasites must be specified by a distinct mechanism. This project aims at uncovering the histone modifications that mediate trypanosome heterochromatin formation. Next-Generation mass spectrometry analysis will be performed to survey histone modifications in the different developmental forms of T.brucei. Additionally, the composition of the trypanosome heterochromatin will be characterised using several alternative strategies including: fluorescent tagging of putative readers, writers and erasers of heterochromatin-associated histone modifications; isolating trypanosome nuclei and enriching for lamina-associated chromatin; and CRISPR/Cas9 or TAL targeting of GFP to repetitive elements in T.brucei.
Successful cell division relies on faithful chromosome segregation. Central to this process is sister chromatid cohesion by cohesin that topologically entraps sister chromatids. Cohesin shows increased association with chromosomal regions surrounding the centromere, called pericentromeres. Pericentromeric cohesin is crucial during both meiosis and mitosis. In meiosis I, when homologous chromosomes segregate, pericentromeric cohesion is protected from separase-dependent cleavage ensuring that sister chromatids stay together until they segregate in meiosis II. In mitosis and meiosis II, pericentromeric cohesin facilitates chromosome biorientation by establishing preferred kinetochore geometry for capture by microtubules. How exactly pericentromeric cohesion facilitates chromosome biorientation is unknown. It was proposed that pericentromeric cohesin establishes intramolecular linkages allowing the pericentromere to adopt a cruciform structure. This would facilitate a back-to-back geometry of kinetochores and would promote kinetochore capture by microtubules from opposite spindle poles. This project aims to characterise the conformation of the pericentromere in budding yeast. I will examine how the conformation of pericentromeric chromatin responds to the presence and absence of tension that is exerted on chromosomes during biorientation. The research will extend to mitotic and meiotic cells, with wild type and cohesin-deficient backgrounds. Ultimately, this will further our understanding on how kinetochore geometry facilitates accurate chromosome segregation.
Single-cell genomics is a fantastic tool for studying developmental biology: it allows unbiased and large-scale study of gene expression at the correct resolution for cell fate decision making. New fluidics systems provide the capability to study tens of thousands of cells simultaneously - as many as there are in the young embryo. For my PhD, I will analyse scRNA-seq data generated on this platform, studying mouse gastrulation between E6.5 and E8. I will be able to study this process at both an exceptional cell-level resolution (thanks to the fluidics) and at an unprecedented time resolution, at 0.1 day intervals. My focus will be on identification of lineage specification, and how cells make their fate choices. I will need to develop new methods to account for the large numbers of cells assayed, the numerous lineage decisions made, and heterogeneity of speeds of development across and between embryos. I hope to produce a map of lineage specification from epiblast (E6.5) cells through to every cell type present at E8. This work will provide a developmental atlas through gastrulation, and general inferences on cell fate decisions may provide insight for cellular reprogramming and regenerative medicine.
Understanding the Pathogenesis of Inflammatory Bowel Disease via Whole-genome Sequencing 31 Jan 2017
We will use a new whole-genome deep-coverage IBD dataset (15x+ coverage, 20 000 cases, 50 000 controls) to conduct genetic association studies. Several analyses are currently planned. The first study will use the data from >1000 IBD patients, who are part of a deep clinical phenotyping experiment, on their response to treatment with anti-TNF medication. We are hoping to determine specific genetic variants associated with successful treatment, non-response, loss of response, and unfavourable drug reactions. Once more samples are sequenced, we will attempt to discover novel low-frequency, rare, and very rare genetic variants associated with IBD. A recent low-coverage sequencing study has identified a rare missense variant in ADCY7 that doubles the risk of ulcerative colitis. In addition, a burden of very rare, damaging missense variants in genes associated with Crohn's disease was detected. The increased coverage and the size of the dataset may confirm the significance of such variants. Discovery of novel rare variants brings important insights into IBD biology, and improves the overall understanding of the genetic landscape of complex diseases.