- Total grants
- Total funders
- Total recipients
- Earliest award date
- 20 Nov 1998
- Latest award date
- 05 May 2020
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
My aim is to complete a quantitative analysis of the dynamic signalling pathways that control mitosis. By combining mass spectrometry with cutting-edge microsopy I intend to measure the number of active molecules of the key mitotic regulators and determine how and where they interact to generate a highly responsive signal transduction network that ensures genomic stability by controlling sister chromatid separation and mitotic exit. I have four main aims: 1) Measure the numbers of the mitotic regulators controlling chromosome separation and analyse how they are modulated by post-translational modifications (PTMs). 2) Determine the dynamics of the spindle assembly checkpoint (SAC) in living cells by measuring the generation of the SAC effector complex and the flux of its components through the pathway. 3) Determine how changes to a kinetochore affect its ability to catalyse the generation of the MCC. 4) Determine how a defined change in the number of molecules of specific regulators alters the dynamics and strength of the SAC, and in consequence their effect on genomic stability. Together, these studies will be used to inform and discriminate between models of mitotic control to determine how the SAC combines the properties of potency and responsiveness.
Genome-wide association studies (GWAS) have identified greater than 450 common low-penetrance susceptibility single nucleotide polymorphisms (SNPs) for various cancers. Approximately one third of these SNPs map to genomic regions harbouring multiple cancer-SNP associations. This project aims to investigate the properties of "pleiotropic" cancer risk SNPs and derive insights into their effect on tumour development. We will initially extract all reported cancer risk-SNP associations with P -8 and use linkage disequilibrium metrics between risk SNPs at nearby genomic locations (e.g. within 1Mb) to determine if they represent distinct or shared association signals. Where available we will make use of tumour and normal tissue mutation, epigenomic, Hi-C and expression data to determine the likely molecular mechanism underlying cancer risk associations, for example regulating target gene expression. Combining all these analyses we aim to classify regions with multiple cancer associations as those exhibiting a) genuine pleiotropy, where the same association signal is shared by multiple cancer types; b) shared molecular mechanism but distinct disease-specific signals, suggestive of tissue-specific regulation; c) shared location by chance, where both disease-association signal and molecular mechanism appear distinct.
Pathogenic Neisseria species continue to cause harmful infections in humans. Neisseria meningitidis causes life threatening meningitis and septicaemia infections, particularly in infants, and Neisseria gonorrhoeae causes the sexually trasmitted infection gonorrhoea. There is an urgent need to further study these pathogens particularly N. gonorrhoeae as gonorrhoea cases are on the rise and it is increasingly in the news due to the sharp increase in cases with resistance to antibiotics, leading to the fear that gonorrhoea could soon become untreatable. We will investigate the role that toxin/antitoxin modules play in Neisseria biology. In other pathogens, these systems have been observed to include a toxin able to stall bacterial replication and an antitoxin that neutralises the toxin's activity. When under stress, the antitoxins are degraded leaving a free toxin to arrest bacterial growth. In this non-growing state bacteria are tolerant to antibiotic challenge. There is very little known about how the toxins of Neisseria function and what their role is in infections. This proposal will address this lack of knowledge by discovering the biological systems targeted by the toxins and assessing their effect on Neisseria metabolism.
Recognition, activation and targeted degradation of protein kinases clients by the HSP90-molecular chaperone 10 Apr 2018
Many oncogenic protein kinases depend on interaction with the HSP90 molecular chaperone, mediated by the co-chaperone CDC37, for their cellular stability and oncogenic activity. Inhibition of HSP90's conformationally-coupled ATPase mechanism leads to the ubiqtuitylation and degradation of these protein kinase 'clients'. Consequently HSP90 is an important target for therapeutic intervention in cancer. Although there has been substantial progress in this field, important issues remain unresolved. In particular we wish to understand : How protein kinase clients are specifically and selectively recognised by the CDC37 co-chaperone, and recruited to HSP90 ? What structural and biochemical changes are elicited in the client protein by recruitment to HSP90 and by its conformationally-coupled ATPase cycle ? How dephosphorylation of CDC37 by the HSP90-targeted protein phosphatase PP5 regulates client protein release ? How protein kinase clients are targeted for proteasomal degradation when HSP90's ATPase is inhibited ? To address these questions we will use cryoelectron microscopy, X-ray crystallography, NMR spectroscopy, and a range of biochemical and biophysical approaches, to determine structures of key complexes along the pathway from initial client recognition to release or ubiquitylation, and define the structural and biochemical transitions that connect them.
rs3817198 at 11p15.5 is associated with estrogen receptor-positive breast cancer risk. This locus shows a parent of origin effect and effect modification by parity. Fine-scale mapping of this region identified seven possible single nucleotide polymorphisms (SNPs), all within 11kb of the 5’ end of Lymphocyte Specific Protein (LSP1), any of which could be causally associated with risk. Four of these map within a region that shows differential methylation and one of them (rs686722) co-localises precisely with a CpG methylated site. We hypothesise that rs686722 influences breast cancer risk because both the allele (C/T) and the methylation of the "C" affect expression of LSP1. The mechanism by which LSP1 could influence breast cancer risk is not clear; one possibility is via an effect on the motility of lymphocytes within the breast stroma. For this project we will use lymphocyte DNA from women participating in the Generations Study and CEPH individuals. The key goals are to investigate the methylation of rs686722 with regard to the parental origin of a woman's C allele and her parity. We will also use lymphoblastoid cell lines from heterozygous CEPH individuals to test for allele specific expression of LSP1.
Alpha-GABa receptor modulators for the treatment of cognitive impairment associated with Huntington’s disease 01 Oct 2017
Huntington's disease is a fatal genetic disease characterised by a movement disorder that is accompanied by a decline in cognitive function and changes in mood and behaviour. The decline in cognitive function may precede the movement disorder by a decade or more and is a very important component of the functional disability associated with the disease. There is, however, no effective treatment for enhancing cognitive performance in Huntington's. Professor John Atack at the University of Sussex aims to identify novel drugs that can enhance cognitive performance in subjects with Huntington's disease to address a large unmet medical need.
This proposal is aimed at understanding how repetitive and structure-prone sequences are replicated accurately. Repetitive DNA comprises over half of the human genome. Repeat instability due to unusual DNA secondary structures causes many neurodegenerative diseases and is a diagnostic and prognostic cancer marker. While genetic studies revealed that repeats impair DNA replication and that replication can induce repeat instability, mechanistic insight is lacking. It is therefore crucial to understand how repeats are accurately replicated in normal tissues and how they become unstable in disease. First, I will determine the nature of replication-dependent DNA structures. Building on my recent advances in sequence-specific in vitro replication, I will delineate the effects of DNA secondary structures on replication dynamics, including DNA unwinding, DNA synthesis, Okazaki fragment maturation and replisome stability. Finally, I will discover factors that enable faithful replication of structure-prone DNA using a combination of biochemistry, candidate genetics and proteomics. As a long-term goal, I aim to elucidate the interplay between replication and repair pathways, such as mismatch repair. Altogether, these aims will define the relationship between DNA sequence, structure and replication and may lead to identification of novel factors that modulate the formation and resolution of toxic DNA structures.
The Institute of Cancer Research (ICR), in partnership with the Structural Genomics Consortium (SGC), proposes to assume responsibility for the Chemical Probes Portal (http://www.chemicalprobes.org/) (Portal) and move its operations to the UK. We request funds to complement existing in-kind and financial support in order to: maintain, enhance and expand the Portal; ensure its continuation as an invaluable public resource; and implement a sustainability plan for future independence. The Portal is a public online resource created to provide biomedical researchers with expert advice to identify the most appropriate chemical probes for their experiments. Experts rank probes using a star rating and provide advice on their properties and use. It is an innovative, open science solution with a clear aim – to reduce the use of poor quality probes in the literature, and thus increase the quality and reproducibility of scientific research. The Portal is currently supported by small donations from companies and in-kind contributions from a founding set of 146 advisors from academia and industry. We are seeking complementary funding from The Wellcome Trust to enhance, extend and maintain the core infrastructure, to expand the number of probes, and to better communicate the Portal’s offering to funders, scientists and publishers.
DNA damage can lead to deleterious mutations, cell death, and is a driver of diseases such as cancer. Although exogenous sources, such as radiation, have long been characterized as DNA damaging agents, we have recently discovered that in normal cells, DNA is also damaged during normal DNA synthesis; leading to cell cycle arrest mediated by the Cyclin Dependent Kinase Inhibitor p21 (p21WAF1/CIP1, CDKN1A) (Barr et al., Nature Communications 2017; Heldt et al., PNAS 2018). The mechanism behind this damage is not clear, but a number of recent studies suggest that mechanical forces, including those generated by the cell's own actomyosin contractile machinery, can damage DNA. Actomyosin contractility is a key regulator of cell shape, and is particularly high when cells are attached to stiff matrices such as in bone or fibrotic tissue, or when cultured on stiff tissue culture plastic. We will determine if actomyosin contractility, generated by the cell’s own cytoskeleton, causes DNA damage during S-phase during proliferation. The student will monitor DNA damage in living single cells during by imaging the dynamics of endogenously tagged p21 after manipulating actomyosin contractility using chemical or bioengineering approaches. This work will provide new insights into the source of endogenous DNA damage.
Exploiting 3D molecular and cellular models of endocrine resistant breast cancer to identify new therapeutic strategies 30 Sep 2018
Breast cancer is one of the most common cancers in the world. One of the treatments is the use of drugs that block the action of hormones that can help the cancer grow. However, while 80% of breast cancers can initially be treated this way, half of these will develop resistance to these drugs, and start to grow and spread again. There has been a lot of research thus far into how the cancer changes to circumvent these drugs using 2D models, by mimicking the treatment conditions and examining how breast cancer cells adapt on a molecular level, but the answer still eludes us. This project aims to develop 3D models of breast cancer – so that the experiments more accurately reflect how the cells exist in the patient – and then subject these models to different genetic interferences and drug conditions, to see if we can find the key drivers in the cells that confer resistance to endocrine therapy. We then hope to identify drugs that can block these drivers, to find new therapeutic strategies for treating endocrine resistant breast cancer.
The aims of the project are to develop and select the most effective maraba oncolytic viruses (OV), encoding genes into the maraba virus in order to enhance an anti-tumour response through immune priming, to be taken forward into clinical testing for the treatment of advanced melanoma.
Enhancing electron microscopy facilities at the University of Sussex with High-Pressure Freezing technology 06 Jul 2017
We are requesting a high-pressure freezer (HPF) and freeze-substitution processor (FSP) at the University of Sussex to substantially enhance our transmission electron microscopy research and meet significant unmet demand. HPF/FSP is now the de facto standard for the highest-quality specimen fixation for ultrastructural work, offering key benefits for protein integrity, ultra-rapid controlled fixation, fluorescence preservation for correlative work and penetrative thick-sample fixation. The requested system includes modules for synchronizing optogenetic/electrical stimulation with freezing onset, offering revealing ‘snapshot’ views of rapid and dynamic events. Collectively, these advantages will open up major new directions for existing research programs within the School of Life Sciences, and wider afield. Planned research includes studies aimed at: defining synaptic vesicle recycling pathways in central and sensory terminals, revealing ultrastructural correlates of disease-related neuronal dysfunction, elucidating chromosomal breakage events during mitosis, investigating ultrastructural determinants of centrosome positioning, and characterizing protein organization in ionizing radiation-induced foci. The School has made major recent strategic investment in developing world-class electron microscopy facilities and the HPF/FSP will offer significant enhancements to this equipment for ultrastructural research. The system will be fully-integrated into the new purpose-built Life Sciences building (completion 2019-2020) ensuring its long-term sustainable use within a state-of-the-art dedicated Bio-Imaging centre.
Clinical PhD Programme in Cancer Research 30 Nov 2016
The Institute of Cancer Research (ICR), a degree-awarding, independent college of the University of London, proposes to host a Clinical PhD Programme in Cancer Research. The Clinical Fellows appointed to this Programme will be embedded in the highly successful translational research culture of the ICR, and our hospital partner the Royal Marsden Hospital (RM). Clinical Fellows will directly contribute to delivering practice-changing research and will be an integral part of the flow of ideas in both directions between the laboratory and the clinic. The Clinical Fellows will participate in, and learn from, research teams working as parts of global consortia on projects as diverse as understanding cell division, MR-guided radiotherapy, novel drug discovery and development; genome damage and stability and big data approaches. We will continue to maximise opportunities to support the career development of Clinical Fellows on this Programme; build on existing good practice in supporting clinical academics, strengthen the provision of training tools, workshops and mentorship opportunities; and facilitate communication and the establishment of collaborative relationships between ICR and RM clinical researchers at different career stages. The ultimate goal of the Programme is to train, develop and support future international leaders in clinical cancer research.
Inhibitors of Lysyl Oxidase for the Prevention and Treatment of Invasive and Metastatic Cancer 02 Oct 2016
The enzyme lysyl oxidase (LOX) regulates cross-linking of structural proteins in the extracellular matrix. LOX also plays a role in stimulating the metastatic spread of cancer through the body. Its expression is increased in hypoxic cancers and is correlated with tumour metastasis and decreased patient survival. In model systems its inhibition significantly decreases cancer metastasis and increases survival. Since metastasis is responsible for over 90 per cent of cancer deaths these data validate LOX as an important therapeutic target in cancer. Professor Caroline Springer and Professor Richard Marais from the Institute of Cancer Research have been awarded Seeding Drug Discovery funding to develop drugs that target LOX. They are applying a medicinal chemistry drug discovery approach underpinned by a strong programme in LOX biology with the aim of producing orally available, small molecular weight drugs that inhibit LOX activity for cancer treatment.
The serendipitous discovery of new targets of drugs questions the prevalent view of drugs as selective inhibitors of a single protein. However, how the binding to several proteins – termed polypharmacology – influences clinical safety and efficacy is poorly understood. During this project, I will analyse clinical, omics and chemical data to uncover the impact of polypharmacology in precision oncology. Firstly, I will analyse data from clinical trials performed at the Royal Marsden Hospital to identify the drugs taken by patient super-responders or those drugs that produced unexplained side-effects. This clinical data will be integrated with chemical data available via the knowledgebase canSAR and used to predict polypharmacology using recently developed chemoinformatic methods. Predicted off-tragets will then be experimentally validated. Finally, I will use available clinical and omics data to identify predictive biomarkers of the newly identified off-targets. Overall, I propose a unique project that has not been attempted before due to the combination of multidisciplinary skills, data and environment required. This project has the potential to transform our understanding of drug action and to yield new biomarkers that can quickly be translated to extend the use of existing cancer drugs in the clinic for the benefit of cancer patients.
Vacation Scholarships 2017 - Institute of Cancer Research
Testicular germ cell tumour (TGCT) has a strong inherited basis with brothers of cases having a 6—10 fold increased risk of disease and heritability of >45%. Whilst GWAS studies have identified >25 loci associated with disease, the underlying causative variants and mechanisms for conferring susceptibility to the disease are poorly understood. Furthermore, whilst recent whole exome analysis had implicated rare variants in genes related to microtubule and ciliary function in familial TGCT, these rare variants only account for a modest proportion of disease heritability. To date there has been no exposition of the role of copy number variation in susceptibility to TGCT and it is plausible that copy number variants may contribute to the "missing heritability" of TGCT. Furthermore, identification of copy number variants implicated in TGCT susceptibility may be informative with regard to highlighting novel TGCT susceptibility genes located within the regions of copy number variation. In this project I shall deploy copy number-calling algorithms on (i) SNP array data on 7319 TGCT cases and 23082 controls and (ii) whole exome sequencing data on an overlapping set of 962 TGCT cases and 1644 controls.