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Results

Investigating the Structure of FcγRIIa and its Interactions within the Membrane 30 Sep 2018

Human Fcgamma receptors (FcgammaRs) are proteins found on the surface of immune cells. They bind to antibodies, which are produced by the body, in response to infection. Some antibodies produced recognise their own tissues and are found in many diseases, including rheumatoid arthritis and lupus. It has been shown that genetic changes in the FcgammaRs are found more frequently in rheumatoid arthritis sufferers compared to healthy individuals. This project will focus on FcgammaRIIa, which is present on cells which are responsible for the destruction of many antibody-bound objects. Through a combination of cutting edge techniques, spanning physics, biology, immunology and medicine, we will uncover fundamental information within this field. This information would aim to inform the production of effective therapies to treat diseases such as arthritis, which put a huge strain on the NHS every year.

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

A structural investigation into the action of and resistance to ribosome-targeting antibiotics 30 Sep 2018

Antibiotics are crucial to modern medicine, allowing treatment of life-threatening bacterial infections and making many surgeries like transplantations possible. However, pathogenic bacteria are rapidly evolving to resist their effects. Protein synthesis is one of the main antibiotic targets in bacterial cells. I will use structural biology techniques, principally cryoEM and single particle image processing, to understand how both novel natural products and clinical antibiotics bind to the ribosome to bring about their inhibitory effects on protein synthesis. Furthermore, I will investigate the cause of toxicity of certain ribosome-binding antibiotics by examining how they bind to the mammalian mitochondrial ribosome. Finally, I will use a combination of cryoEM and protein X-ray crystallography to elucidate how certain ribosomal-protecting proteins form complexes with the ribosome in order to bring about antibiotic resistance. On an individual level, these studies will allow an assessment of the viability of novel natural products as suitable clinical antibiotics. More generally, they will contribute to our knowledge of how different classes of antibiotics target the ribosomes of pathogenic bacteria, and how these bacteria evolve resistance. This knowledge will help the development of methods to rationally design new ribosome-targeting antibiotics that are able to overcome or circumvent resistance.

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

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

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

Functional characterization of a novel KMT2D-related developmental disorder 31 May 2018

The proposed research uses standard molecular biology, protein purification and biophysical structural analysis methods in a focused series of experiments that comprise a complete 6-week project. This builds on existing molecular genetics studies that have identified novel missense mutations in KMT2D (also known as MLL2) as the cause of a unique phenotype (renal tubular dysgenesis, choanal atresia and athelia). Previous studies have identified KMT2D mutations as a major cause of Kabuki syndrome, a comparatively common autosomal dominant congenital mental retardation syndrome. The missense mutations occur in a central region of the KMT2D protein (2841-3876) that does not have variants associated with Kabuki syndrome. This central region contains a series of coiled-coil domains that are likely to mediate protein-protein interactions. However, the effect of the missense mutations on KMT2D structure and interactions is completely unknown. This project will determine the structure-function relationships between KMT2D and a unique phenotype that are likely to be caused by altered protein-protein interactions, as well as describing the broader genotype-phenotype correlations in this important gene. The approach described in the proposal is the only tractable way to understand possible structure-function relationships, given the large size of the gene and encoded protein.

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

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

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

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

Revealing how extracellular matrix glycans define chemokine gradients 31 May 2018

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.

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

Regulated mRNA stability and translation in neural stem cell development 28 Nov 2017

Understanding how the billions of varied cells in the human brain develop from a small number of neural stem cells (NSCs) is a central question in biology and medicine. This highly complex process has largely been explained by transcriptional regulation dictating the levels of protein expression in stem cells and their progeny. Using novel single molecule approaches to quantitate transcription and protein levels, we have discovered functionally important conserved examples where the levels of transcription and protein expression do not correlate. These include pros/prox1, the regulator of NSC proliferation and differentiation and myc, the proto-oncogene regulator of stem cell size. We will characterise the mechanism of post-transcriptional regulation of pros, myc and 21 additional functionally important examples we have discovered, all of which have extremely long 3’UTRs that are bound and regulated by the same conserved RNA binding proteins, Syp and Imp. We will also measure, genome-wide, mRNA stability and characterise the trans-acting factors and cis-acting signals regulating stability and translation. The proposed programme will characterise a hitherto under-studied layer of regulation acting in addition to transcription in complex tissues, providing major new mechanistic insights into how the brain develops in health and disease.

Amount: £1,972,007
Funder: The Wellcome Trust
Recipient: University of Oxford

Specialised Ribosomes – Does KSHV modulate ribosome composition 30 Sep 2018

Historically, ribosomes have been viewed as unchanged homogeneous units with no intrinsic regulatory capacity for mRNA translation. Recent research is shifting this paradigm of ribosome function to one where ribosomes may exert a regulatory function or specificity in translational control. Emerging evidence has identified heterogeneity of ribosome composition in specific cell populations, leading to the concept of specialised ribosomes. Specialised ribosomes may therefore exhibit control and regulation over the translation of specific mRNAs, resulting in a substantial impact on how the genomic template is translated into functional proteins. Due to the emerging concept that cells can control the composition of ribosomes to regulate protein expression, it would seem highly likely that viruses could also manipulate host cell ribosome compositions to enhance the production of viral proteins. We have quantitative proteomic and ribosomal profiling data suggesting Kaposi's sarcoma-associated herpesvirus (KSHV) manipulates ribosomal biogenesis. Firstly, we will investigate changes in composition and stoichiometry of proteins within the ribosome, driven by KSHV. We will isolate ribosomal complexes by tandem affinity purification, during KSHV infection and analyse changes by LC-MS/MS and cryo-EM. We will elucidate how these changes exert ribosome-mediated specificity to promote KSHV lytic infection using a number of cellular and molecular techniques.

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

Understanding the role of retinoic acid in cyanobacteria 31 May 2018

We will be investigating the viability of using cyanobacteria as a model for our own by exploring the evolutionary links as well as the similarities between human cells and cyanobacteria cells in terms of the communication and cell differentiation. This will allow us to use the cyanobacteria as a model for human stem cells. There are 3 cases which will be investigated: metabolism of retinoic acid, nitrogen-fixing cells and prostaglandin cell signalling. In each case, we will be blocking the signal, modifying the bacteria and studying how this affects the bacteria. The production of proteins and the chemical signalling are amongst the several responses we will be monitoring. Using information gained from this we will be able to see if there is a viable link that can be used to monitor cyanobacteria that have human orthologues spliced into it.

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

Investigate the role of SET1A in the activation of gene expression 30 Sep 2018

The regulation of gene expression is fundamental for cellular integrity and is partly achieved by the opposing action of repressive and activating histone modifications. One such histone modification is the tri-methylation of lysine 4 on histone H3 (H3K4me3), which is known to correlate with transcriptional activity. The SET1A complex is responsible for depositing the majority of H3K4me3 in mammalian cells and disrupting its function often leads to gene expression defects. However, the mechanisms by which SET1A regulates gene expression remain unknown. I will use the auxin-inducible degron system to rapidly deplete SET1A levels. A series of genomics technologies, including ChIP-seq and NET-seq will then be used to determine the effects of SET1A loss on chromatin architecture and transcriptional activity. Additionally, proteomics techniques will be used to identify the pathways perturbed upon SET1A loss, hence identifying the mechanisms by which SET1A supports active transcription and furthering our understanding of how gene transcription is regulated. This is essential for the development of novel therapies targeting genetic diseases in which the control of gene expression is perturbed.

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

Dengue Controlled Human Infection Model - Development Grant 17 Nov 2017

Following a positive response to the preliminary submission for grant funding to establish a Dengue Controlled Human Infection Model (Dengue-CHIM ) in Ho Chi Minh City, Vietnam, I am submitting this request for a small grant to assist in refining and developing the main proposal prior to final submission in March 2018. During this pre-submission phase I plan to employ an experienced post-doctoral immunologist to carry out a) a scoping review of the current landscape of dengue vaccines in development, and b) a review exploring the current understanding of the immune response to/protection from DENV infection and disease, particularly focusing on immune correlates of protection. This will be the first application of a Dengue-CHIM approach in any dengue endemic setting, and raises a number of important bioethical concerns. Therefore I also plan to employ a Vietnamese social science research assistant for a period of 4 months to engage with key Vietnamese stakeholders to discuss the important issues surrounding endemic setting CHIMs, conduct preliminary informal interviews with these individuals, and help to develop the agenda for a 2 day workshop focused on Bioethics and Stakeholder Engagement related to endemic setting CHIMs that will take place in early March.

Amount: £23,690
Funder: The Wellcome Trust
Recipient: University of Oxford

How is transcription factor function impeded during X chromosome silencing? 30 Sep 2018

In the nucleus of every cell DNA is present as pairs of parentally-inherited chromosomes, from which genes are expressed to perform biological functions. In most mammals, including humans and mice, females tend to have two X chromosomes whereas males have one X and a Y chromosome, which lacks most of the genes present on the X. Thus in order to ensure that the dosage of gene expression from essential X-linked genes is similar between both sexes, almost all genes on one female X chromosome are silenced during development. X inactivation is mediated by a long non-coding RNA, Xist, which spreads to coat the chromosome and coordinates silencing through the recruitment of relatively few factors implicated in specific chromatin remodelling pathways. Beyond its intrinsic biological significance in mammalian development, it is a tractable model system for investigating general molecular mechanisms by which chromosomes are silenced. My reseach will focus on the question of how transcription factors that normally bind enhancers and promoters to activate genes are prevented from performing their functions as the X chromosome is silenced. I will investigate this question in cellular and in vivo models of X inactivation, including in mutant cell lines defective for chromosome silencing.

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

Grb2-mediated regulation of miRNA maturation in the basal state. 30 Sep 2018

Cancers develop as a result of many interacting factors. Two such factors are cell stress and microRNA (miRNA) expression. Cell stress causes fluctuations in protein levels, which can perturb the proper functioning of the cell. miRNAs silence specific genes, and therefore can induce changes within the cell which cause them to become cancerous. However, little is known about how miRNA expression is altered. I aim to investigate a novel mechanism of miRNA regulation, which may be perturbed by cell stress. I will determine how the levels and activity of key components in miRNA biogenesis are altered in cells expressing different proteins and which have been subject to different stress conditions, using a range of in vitro, cell-based and biophysical approaches. I will also perform several screens to identify key microRNAs regulated by this mechanism, and how their expression changes with cell stress. This work will reveal new avenues for cancer therapy and help us to target cancer with a fresh perspective.

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

Brain regulation of feeding behaviour through mitochondria fission 21 May 2018

Obesity causes brain insulin resistance and prevents the brain from regulating metabolic responses, maintaining energy balance and controlling the nutritional status of an individual. Restoring the brain’s ability to modulate metabolic functions could be an important intervention to prevent the negative outcomes of obesity and diabetes. The Dorsal Vagal Complex (DVC) in the brainstem senses insulin to regulate glucose metabolism, food intake and body weight in rodents. Three days of high-fat diet feeding is sufficient to completely disrupt the insulin response in the DVC, thus causing an increase in blood glucose levels and excessive eating. Recently, I discovered that increased mitochondria fission and ER stress in the DVC can cause insulin resistance and affect the ability of the DVC to regulate blood glucose levels. I aim to understand whether increased mitochondria fission in the DVC can affect food intake and body weight in rats. Using in vivo and in vitro experiments, I aim to uncover the mechanism by which changes in mitochondria shape and size affect DVC insulin sensing and eating habits in rodents. This project could lead the way for the development of novel approaches that target the brain to regulate food intake and body weight in obese subjects.

Amount: £99,948
Funder: The Wellcome Trust
Recipient: University of Leeds

Peripheral gate in somatosensory system 17 Jul 2018

Peripheral nerves are responsible for haptic, somatic and visceral sensations including that of pain. Healthy nerves conduct action potentials from their peripheral endings to the dorsal spinal cord, where synaptic transmission first takes place. It is assumed that the peripheral somatosensory signals are first integrated in the spinal cord and subsequently analysed in the brain. Our recent findings has challenged this view and suggested that peripheral somatosensory ganglia (such as dorsal root ganglia, DRG) are capable to regulate pain transmission utilising GABAergic somatic cross-talk mechanisms. I hypothesize that somatosensory ganglia represent a new type of a ‘gate’ within the somatosensory system. My overarching goal is to develop a comprehensive mechanistic understanding of the peripheral somatosensory gating. I will use in vivo electrophysiology, mouse transgenics, chemo- and optogenetics, behavioural models and other cutting-edge approaches to address the following specific aims. (1) Secure direct in vivo evidence for peripheral somatosensory integration at the DRG. (2) Moving beyond GABA: identify other major ganglionic communication mechanisms. (3) Elucidate physiological context of signal integration in the DRG. (4) Identify subcellular structures involved in somatic integration. These studies will change current understanding of somatosensory processing and will provide new ideas for pain treatment at the periphery.

Amount: £1,141,006
Funder: The Wellcome Trust
Recipient: University of Leeds