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Recipients:
University of Oxford
University of Cambridge

Results

Neural Systems for Decision-Making and Startegy Implementation 09 Apr 2008

The human frontal cortex controls attention, learning, memory, language, decision-making, judgment, and planning, in addition to other different cognitive functions. Damage to the frontal lobes is a frequent consequence of stroke and traumatic brain injury. Impairments in frontal lobe function are also common in Alzheimer disease, Parkinson's disease, and frontotemporal dementia, as well as neuropsychiatric disorders such as obsessive-compulsive disorder, mood disorders, and schizophrenia. Clinically, impairments in these functions make it impossible for people with these ailments to live independently. The available data, although very limited, suggests that these different functions may be regulated by different neurotransmitter systems within the frontal cortex. We need to know the neurobiological bases of cognitive functions controlled by the frontal lobe in order to understand the pathogenesis of cognitive impairment in these various conditions and to design therapies that could ameliorate these impairments. The experiments proposed in this programme of research will use sophisticated behavioural assessments of decision-making, planning, and strategy selection in animal models, to test the effects of selective depletion of particular neurotransmitters within the frontal cortex on these abilities. First we will identify the subregions within frontal cortex that are responsible for particular aspects of these complex cognitive functions, because there is evidence that different areas of the frontal cortex make different contributions to the regulation of behaviour. Then we will use immunotoxins to remove selectively input from a particular transmitter system (acetylcholine, dopamine, serotonin) to subregions of frontal cortex. The promise of this work is a fuller understanding of the neurochemical regulation of prefrontal cortex function, leading to the development of pharmacological agents that could be used to regulate selectively particular cognitive functions controlled by the frontal lobe.

Amount: £818,107
Funder: The Wellcome Trust
Recipient: University of Oxford

Additional funds for the study Implications of bacterial evolution and health: the Neisseria model. 17 Oct 2007

Many pathogens of man are antigenically variable, using changes in the structure of cell components that are exposed to the immune system as a means of evading immune attack. This strategy poses substantial difficulties for the development of public health interventions, particularly vaccination. In addition, the evolution of antigenic variants and the accommodation of such variants within the structural constraints of the cell surface are important fundamental phenomena. The existence of pathogenic species as 'strains' that are antigenically distinct has been known for most of this century but the evolution of 'pathogenic' strains and the reasons for their stability in the face of recombination and diversifying selection remain poorly understood. This project will improve our understanding of the evolution of antigenic variants by the acquisition and analysis of data from populations of the human pathogen Neisseria meningitidis specifically to apply, test, and develop models of the evolution of antigenic variation. The range and rate of antigenic variation in each sub-population of meningococci will be established and the following specific hypotheses will be addressed: (i) that meningococci have a range of population structures that are associated with specific epidemiologies; (ii) that the antigenic diversity of distinct meningococcal sub-populations differ in both level of diversity and in the mutational mechanisms most important in generating that diversity; (iii) that meningococcal populations are structured into strains by human immune interactions, and that any differences observed in (i) and (ii) are the result of differing selection pressures in diverse epidemiological contexts; (iv) that nucleotide sequence data can be used to predict antigens that are likely to be of use in vaccine design. These data will be used to validate and develop further models of antigenic variation and its effect on clonal divergence and epidemiology.

Amount: £185,117
Funder: The Wellcome Trust
Recipient: University of Oxford

Control of antigen processing by Fc receptors. 05 Jun 2008

My proposal seeks to understand how Fcgamma receptors (FcgRs) control antigen processing by dendritic cells and macrophages. Since FcgR subtypes are variably expressed, have different binding affinities for different IgG subclasses and lead to fundamentally distinct patterns of intracellular trafficking and processing, it is not understood how, for a given repertoire of expressed FcgR, a specific antigen will be processed and what programme of effector functions will be triggered. My first key g oal will be to systematically define functional outcomes (binding and internalisation, antigen degradation and presentation) for ligand-receptor combinations using a receptor expression library in U937 cells expressing 90 different patterns of receptor subtype and disease-associated polymorphisms. Findings will then be confirmed using primary cells from healthy volunteers. I will then define the critical signal transduction events responsible for determining immunogenic and tolerogenic antigen p rocessing focussing on 1) the effect of receptor membrane sub-localisation on receptor function and cellular behaviour and 2) the role of macro-autophagy in modulating or possibly mediating FcgR-triggered intracellular antigen trafficking.

Amount: £1,572,010
Funder: The Wellcome Trust
Recipient: University of Cambridge

The control of MHC class I by viral and cellular E3 ligases. 05 Jun 2008

Regulation of cell surface receptors is essential to maintain cell homeostasis, especially following receptor stimulation to limit the duration and intensity of signalling. Receptor ubiquitination is an important mechanism for regulating expression of critical immunoreceptors. The K3 and K5 viral E3 ligases ubiquitinate cell surface class I, promoting its endolysosomal degradation, and we showed an absolute requirement for lysine-63 linked polyubiquitination of class I for its downregulation. Th ese viral genes accelerate a constitutive pathway of class I regulation. Continued studies on K3 and K5 will further define this receptor regulation pathway. Biochemical inhibitors of class I ubiquitination, and RNAi screens will identify the cellular ligase(s) responsible for class I ubiquitination, and establish the role of lysine-63 linked polyubiquitination in regulating class I and other immunoreceptors. Investigations into the viral ligases identified an unrecognised family of cellular lig ases the MARCH proteins, whose expression downregulates surface receptors. We have developed screening and mass spectrometry-based techniques, as well as MARCH9 knockout mice, to identify the substrates and function of these proteins. Biochemical studies on the regulation and expression of MARCH9, together with an analysis of MARCH9 deficient mice will determine the physiological role of the MARCH9 E3 ligase in immunoreceptor regulation.

Amount: £1,655,728
Funder: The Wellcome Trust
Recipient: University of Cambridge

Clinical Characterisation of a Broad Spectrum of Genetic Variation in the General Population 30 Sep 2018

Inborn errors of metabolism (IEM) are severe and extreme changes in metabolism caused by mutations in a single gene. Recent large-scale human studies have shown that genes causal for IEM are associated with nutrients, or ‘metabolites’, in the blood. However, whether these associations cause disease or adverse health outcomes is unknown. In this project, I will use IEM genes identified in these studies to link genetic variation to clinical features in a large human population. To do this, I will assemble a list of IEM genes of interest that were identified in the literature and in large population datasets. I will then test for associations between the variants I find in these genes and a wide range of clinical features found in open-access population datasets. As the IEM genes used in this study have been associated with blood metabolites previously, linking variants in these genes to clinical features will shed light on the molecular mechanisms underlying genes and disease in the general population. Understanding how genetic variation affects disease will help identify novel therapeutic targets and enable health professionals to better manage disease risk.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Cambridge

Investigating non-canonical programmed ribosomal frameshifting in porcine reproductive and respiratory syndrome virus 30 Sep 2018

RNA viruses are under selection pressure to maintain a small genome, however they still need to produce a variety of proteins. To overcome these conflicting pressures, many viruses use non-canonical methods of translation control. One example of this is programmed ribosomal frameshifting (PRF), in which a percentage of ribosomes, while translating a ‘slippery sequence’ slip one or two nucleotides out of frame, consequently translating the remainder of the mRNA in a different reading frame and allowing expression of more than one protein from a single gene. This is normally stimulated by a downstream secondary RNA structure, however there are two known examples of a trans-acting viral protein being used as the stimulatory element. One example is found in the genome of porcine reproductive and respiratory syndrome virus (PRRSV): an Arterivirus that infects pigs, causing an estimated annual cost to the US swine industry of $664m. I will use structural techniques such as X-ray crystallography to derive information about the RNA/protein complex, and will investigate the efficiency and mechanism of this non-canonical PRF using ribosomal profiling in parallel with RNASeq. The latter will also allow me to analyse host and viral gene expression, to examine host-virus interactions in this important pathogen.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Cambridge

Novel statistical methodology for rare variant association in a case-control cohort 30 Sep 2018

Genetic association studies focusing on common variation have uncovered only a fraction of proposed trait heritability. Some of this so-called missing heritability will be found within rare variation in the population. This hypothesis is supported by the facts that recent explosive population growth has increased the population burden of rare variants and deleterious variants are kept at low allele frequencies. All genetic susceptibility to disease is caused by alterations to the genes or their expression and for this reason it seems fruitful to focus an association study on the genes themselves. Any associations found are then directly informative about the molecular basis of disease without the need for fine mapping. The proposed project aims to develop a statistical method to find genes associated with disease by analysing the rare variation present in a case-control cohort. We aim to extend existing methods by including a previously unconsidered parameter; the position of the variants in a gene. In scenarios where differences in clustering or distribution of variants are observed between cases and controls, this method will have a substantial increase in power. This technique will be useful for elucidating the molecular mechanisms causing the disease and thus discovering new therapeutic targets.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Oxford

Epigenetic inheritance: the influence of variable silencing of the repeat genome. 10 Apr 2018

Evidence from epidemiological studies and experiments in animal models suggests that effects of environment and lifestyle can be transmitted across generations via non-genetic mechanisms. Such mechanisms are challenging to unravel in mouse and man. In mammals, non-genetic inheritance is best exemplified by the Agouti viable yellow (Avy) mouse where phenotypic differences in genetically identical animals are caused by insertion of a retrotransposon - an endogenous retrovirus (ERV) that provides a cryptic promoter driving ectopic expression of agouti. This ERV is variably DNA methylated in different individuals causing inter-individual variation in coat colour – a non-genetic influence on phenotype. Remarkably, a memory of parental coat colour is transmitted to subsequent generations. Variable expressivity can be modulated by in utero environmental exposures. ERVs represent ~12% of the mouse genome. Inspired by Avy, we propose a research programme, supported by preliminary data, to address the following questions: Aim 1 – To what extent do mammalian ERVs exhibit variable epigenetic silencing and what is the mechanism? Aim 2 – Is this transmitted as non-genetic memory across generations? Aim 3 – Are they sensors of environmental compromise? Aim 4 – Are there implications for phenotype? Aim 5 – Does a related phenomenon occur in humans?

Amount: £2,929,851
Funder: The Wellcome Trust
Recipient: University of Cambridge

Gene Expression Heterogeneity in the Maintenance and Coordinated Differentiation of Neuromesodermal Progenitors in vivo 08 Aug 2018

Modern imaging data in biology is essentially multi-scalar in that raw image data undergoes a series of processing steps until it is at a manageable size to perform quantification and analysis. While this processing pipeline might be beneficial to one set of scientific questions, it may be inappropriate to others. Computational biologists may be interested in improving the pipeline itself, while other researchers may be interested in accessing the already processed data. Thus, a central road-block in the open sharing of large-scale imaging data is the fact that there is no one size fits all solution. This project aims to generate a web-based database that stores experimental and data descriptors together with links to the raw and processed data files. This will greatly enhance our ability to upload this data to repositories that are based placed to share the datasets in question, from the raw unprocessed data files down to feature extracted and processed data. Upon submission, the website will link to the deposited data and thereby act as an integrated platform for other researchers to access and explore the data that is available to them. Thus, researchers will be able to access our data at all levels. In built in the project is a second evaluation phase, whereby will we reach out to collaborating laboratories to assess the effectiveness of our open research platform. These will include computational biologists interested in accessing raw data files and processing pipelines, and other developmental biologists who will interact with processed datasets.

Amount: £48,563
Funder: The Wellcome Trust
Recipient: University of Cambridge

Design and evaluation of a modified vaccinia Ankara vector therapeutic vaccine for hepatitis B immunotherapy 30 Sep 2018

Hepatitis B virus (HBV) is a serious global health problem, with approximately 240 million people chronically infected. Long-term infection can lead liver failure, cancer and death. Current therapy controls but does not eradicate the infection. T cells are a type of immune cell necessary to fight HBV. During chronic hepatitis B these cells become less active. Checkpoint inhibitors are a form of immunotherapy that enables T cells to function again. In a study of woodchucks infected with a similar virus to HBV, treatment with vaccine and checkpoint inhibitor lead to better control of the virus. This project aims to use this combination of vaccine and checkpoint inhibitor, to treat patients with chronic HBV. A vaccine using a virus to carry the HBV proteins has been developed and shown to generate good immune responses in mice. We plan to develop a second vaccine to boost this response and test the vaccines together with checkpoint inhibitors in mice infected with the HBV virus. This will allow us to assess how effective this is at eradicating HBV. If the results from this study are promising, this could pave the way for clinical trials in humans with chronic HBV.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Oxford

Probing nucleotide interactions with Kir6.2 using fluorescence spectroscopy. 30 Sep 2018

The ATP-sensitive potassium (KATP) channel is a plasma membrane protein present in beta cells of the pacreas which plays a key role in insulin secretion. KATP acts as a metabolic sensor, alerting the beta cells when blood glucose raises too high and stimulating them to release insulin. In diabetes, normal KATP function is disrupted and beta cells no longer secrete insulin properly in response to blood glucose levels. The molecular structure of the channel is closely linked to its function; there have been several genetic studies linking various mutations (which often only affect one molecule in the channel!) to neonatal diabetes or increased propensity to type II diabetes. Our research aims to identify precisely how these small mutations can have such drastic changes in the activity of the channel by using a combination of fluorescent labels and channel current measurements to watch the KATP channel move in real time. We can then try to construct a model of how the channel converts different stimuli into movements, and how this is affected in mutations linked to diabetes.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Oxford

Learning the Signatures of Cancer 30 Sep 2018

Cancer is a genetic disease that is the second leading cause of death worldwide. Developing effective personalised therapies requires characterisation of the genetic factors driving malignancy. This is challenging as cancer is highly complex, heterogeneous, and dependent on cellular context. Cancer stratification aims to group cancers that share similar features, and are therefore likely to respond similarly to treatment, however, current stratification methods ignore many important genetic and epigenetic markers that likely influence cancer pathology, which would result in sub-optimal treatment. We propose to use whole genome-and-epigenome profiling and machine learning to extract clinically meaningful features of the host and cancer genomes that can be used to improve patient stratification and reveal novel cancer subtypes. As a proof of principle, we will apply these methods to predict the site of origin in patients with metastatic cancer but unknown primary (CUP), which could help improve diagnosis and prognosis for patients with this complex disease. We envision the robust stratification of cancer patients using genome profiling could lead to direct prediction of optimal treatment decision for all cancer patients.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Oxford

Spontaneous and induced network dynamics across cortical layers during waking and sleep in mice 30 Sep 2018

No one can live without sleep. Even if we try very hard to stay awake, we ultimately can’t resist to fall asleep. Various brain functions, such as the abilities to remember and concentrate, decline when we get tired and improve with sleep. Therefore, it is thought that especially the brain needs sleep and determines when it is time to disconnect and recover. The goal of my research is to understand the brain machinery, which controls sleep and wakefulness. My research requires working with mice as I need to use a genetic tool to switch on and off specific brain cells for a short period of time to find out their role in sleep regulation. I will observe whether the brain can still coordinate its systematic shut down when we turn off cells, which are thought to measure the duration of wakefulness and initiate sleep. I aim to find out whether specific cells can measure how long the brain has been awake and send out signals to coordinate the systematic shut down of many brain regions when falling asleep. I hope that my experiments contribute to an understanding of healthy and disturbed sleep.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Oxford

Lineage tracing and early embryonic dynamics using mosaic somatic mutations 30 Sep 2018

Every cell in the human body descends from the fertilised egg cell, and during the journey from zygote to adult cell, many mutations are acquired. The mutations that happen early enough during embryonic development will be present in some parts of the body, but absent in others. One of the difficulties of this project is the discovery of these early embryonic mutations, as they are hard to distinguish from mutations that happened later in life, noise from experimental procedures, and mutations that were already present at fertilisation. Here, we cut out small pieces of various tissues from multiple individuals using a laser and sequence its DNA. Mutations shared between different samples from the same individual are candidate embryonic mutations. Each mosaic mutation gives us information on the development of the human body and with enough mutations, we can construct and visualise the human body as a large evolutionary tree, with the fertilised egg cell as the single root, and all the adult cells as its leaves. This can give us many new insights on the developmental relationship between different organs, how many different early embryonic cells give rise to one tissue or organ and developmental lineages of different cell types.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Cambridge

The effect of nutrients on maximal fat oxidation rates in adult humans measured using indirect calorimetry. 31 May 2018

I aim to study the effects of nutrient availability and mitochondrial transport capacity on the variability of maximal fat oxidation (MFO) during exercise in healthy adults. Less than half of MFO can be predicted by variables such as gender, VO2max and body composition. There are two possible reasons for this. First, nutrient availability may have a large effect on MFO and current protocols may not adequately control for it. Second, VO2max - which combines two variables with opposite effects on MFO (oxygen uptake and fat mass) - may not be the optimal predictor. Here, I will test whether heart rates at a given power are a better predictor of MFO and whether short-term fluctuations in nutrient availability can explain some of the variability of MFO seen within the general population. Nutrient availability will be altered using a glucose meal and by glycogen depletion. I will also use nitrate supplementation to test whether MFO can be increased by induced-expression of fat oxidation enzymes. The key goals are to determine to what extent short-term changes in nutrients and the expression of fat oxidation enzymes can alter MFO and whether the resultant fat oxidation rates can be predicted using simple heart rate data.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Cambridge

Leveraging genetic variation to understand chromosome pairing, meiosis and the evolution of human disease risk 17 Jul 2018

We have the following specific aims: To discover how normal pairing (synapsis) of homologous chromosomes during mammalian meiosis is genetically controlled in fertile and infertile individuals, and how synapsis first initiates, and then spreads. To do this, we will leverage naturally occurring genetic variation. Errors in recombination, and in synapsis, result in aneuploidy events, and chromosomal rearrangements due to NAHR, that cause many human disorders including infertility, pregnancy loss, cancer, and developmental syndromes. To quantify how the chromatin accessibility and gene expression environments change during meiosis, using single-cell ATAC and RNA sequencing, and learn how proteins binding to DNA coordinate the onset and progression of meiosis, recombination, synapsis and impact fertility, and are impacted by genetic variation and chance. To build from our existing approaches to understand population structure, in order to infer trees revealing the historical relationships relating hundreds of thousands of modern and ancient individuals, in humans and other recombining species. We will use these trees, which change along the genome due to recombination, to investigate how variation impacting complex diseases and other traits has arisen and been acted upon by natural selection, how selection changes through time, and how the rate of evolution itself evolves through time.

Amount: £1,579,531
Funder: The Wellcome Trust
Recipient: University of Oxford

Understanding the Initiation of Viral Replication & its Role in Influenza Virus Pathogenicity 31 May 2018

The development of novel strategies against influenza viruses depends on our understanding of influenza virus replication and pathogenicity. Both are directly linked to the activity of the viral RNA polymerase, which copies and transcribes the viral genome, and generate aberrant RNA products that are non-contiguous in the viral genome and strong inducers of the interferon response. Despite recent crystal structures of the RNA polymerase, we only poorly understand how it interacts with and copies the viral genome, or how it generates aberrant RNA products. This project aims to use i) structure-guided mutagenesis, ii) in vitro and in vivo activity assays, iii) cell culture-based interferon production assays, to ask if RNA polymerase residues that bind and guide the viral genome are important for the initiation of viral replication and the formation of aberrant RNA products and thereby the pathology of influenza virus infections. The project will contribute to our understanding of the mechanics of influenza virus replication and the identification of putative targets for the development of new anti-influenza virus drugs.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Cambridge

High dose iminosugar treatment: Investigation of a new antiviral mechanism of action 30 Sep 2018

Antiviral iminosugars inhibit endoplasmic reticulum (ER) a-glucosidases I and II (a-Glu), which induces misfolding of viral N-linked glycoproteins. ER a-GluII inhibition leads to the release of fewer infectious viruses in vitro and in vivo, and can protect mice from DENV- and influenza lethal challenge. We observed that inhibition of ER a-GluI can lead to similar life-saving effects in mice, even if enzyme inhibition is short lived and achieved by administration of a single dose of the drug. This is sufficient to create long-lived triglucosylated protein species that can prevent secretion of infectious virus for some time. We aim to understand this process. I first will establish cell lines that can be hosts for the viruses I am investigating in which to re-capitulate in vivo observations. I shall then proceed to identify which protein(s) are responsible for the long-lasting antiviral effect, why they are not degraded, and how they can exert an antiviral effect for longer than enzyme inhibition. This work may lead to new ways of treating viral diseases such as dengue, influenza and hepatitis B, prophylactically and/or therapeutically. Moreover, a field trip to Vietnam is planned to take advantage of clinical samples.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Oxford

Molecular mechanisms of alternative splicing regulation 28 Nov 2017

Alternative pre-mRNA splicing (AS) is a widespread regulatory mechanism enabling individual genes to generate multiple protein isoforms. We have investigated the mechanisms controlling AS events that are regulated during the transition of smooth muscle cells (SMCs) between contractile and proliferative phenotypes. We have shown how the widely-expressed RNA binding proteins (RBPs) PTBP1 and MBNL1 regulate SMC splicing events. Recently, we identified RBPMS as a potential "master" regulator of SMC AS. RBPMS is sufficient to switch AS events to the SMC pattern and its activity is strongly modulated by its own AS and by phosphorylation. Critically, RBPMS is sufficient to switch AS to the SMC pattern in vitro. This offers a unique opportunity to determine the molecular anatomy of regulated splicing complexes. We will carry out detailed mechanistic analyses of RBPMS-regulated splicing using a combination of biochemical, proteomic, single-molecule, and structural approaches including Cryo-EM. We will identify critical regulatory interactions between regulatory RBPs and core splicing factors, and test their importance by genome editing and mRNA-Seq. In a complementary aim, we will investigate how peptide-ligand interactions equip PTBP1 to regulate AS and a range of other post-transcriptional processes, and whether a family of such peptide-mediated interactions extends to related RBPs.

Amount: £1,503,005
Funder: The Wellcome Trust
Recipient: University of Cambridge

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.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Cambridge