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Recipients:
University of Oxford

Results

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

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

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

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

Defining the import mechanism of pyocin AP41 and klebicin G 30 Sep 2018

There is an urgent need to develop new antibiotics against multidrug resistant Gram-negative bacteria such as Pseudomonas aeruginosa and Klebsiella pneumoniae. These organisms are major causes of pneumonia and sepsis, with recent reports identifying hospital isolates of each resistant to all known antibiotics. The present research focuses on the mode of action of a family of antibiotic proteins known as nuclease bacteriocins that have not been developed as antimicrobials, but show promise in animal models of infection. Nuclease bacteriocins are species-specific toxins that are used by bacteria to compete with their neighbours. Although folded proteins these molecules are capable of penetrating the defences of Gram-negative bacteria to deliver an enzyme to the organism’s cytoplasm to degrade essential nucleic acids by an unknown mechanism. Two types of nuclease bacteriocin will be investigated, pyocin AP41 which targets Pseudomonas aeruginosa, and klebicin G which targets Klebsiella pneumoniae. Preliminary computational and experimental work on pyocin AP41 has identified potential candidate proteins involved in its import. This will be followed up with structure and function studies of AP41, a dissection of its import mechanism and new studies on klebicin G, a nuclease bacteriocin that has only recently been identified.

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

Understanding the link between CpG islands and gene transcription 28 Nov 2017

CpG islands(CGIs) are epigenetically specified elements that are intimately associated with over two-thirds of human gene promotors, yet whether CGIs regulate gene expression has remained enigmatic. This gap in our understanding of gene promoter function has serious implications for human health given that CGIs are perturbed in cancer and other debilitating human diseases. We have recently discovered that CGIs are recognized by reader proteins which can regulate gene expression. Capitalising on these advances, I will now discover how CGIs and the proteins that read them control the transcriptional machinery at gene promoters. I will achieve this transformative new mechanistic understanding through a multidisciplinary and hypothesis-driven programme of research that builds on a series of exciting new and unpublished observations to discover how CGIs function to activate(Aim1) and maintain(Aim2) transcription, and test whether CGIs create gene expression switches(Aim3). These new discoveries will help to redefine our understanding of how gene promoters function to control gene expression and will provide the basis on which new therapeutic interventions can be developed for diseases where normal CGI biology is perturbed.

Amount: £2,072,282
Funder: The Wellcome Trust
Recipient: University of Oxford

Dissociation: Developing a Cognitive Maintenance Model and Psychological Intervention 30 Sep 2018

As we interact with the world around us, our experience is a result of the synthesis of our consciousness, memory, sense of identity and perception. In ‘dissociation’, this coherence fails or disintegrates. The disintegration may be sudden – meaning that people experience sudden ‘black-outs’ and amnesia for the intervening time – or gradual, where the person may feel increasingly numb or detached from reality. Chronic dissociation is an important problem for mental health professionals to address because it can cause considerable distress and disruption. It is the strongest predictor of a person making multiple suicide attempts, and is thought to underlie self-harming behaviour (such as ‘cutting’). Dissociation is not just experienced in ‘dissociative disorders’, but also across many different psychiatric disorders, including up to 50% of people with psychosis. The aim of this project is to develop and test a new psychological explanation of dissociation as it occurs in psychosis. First, experiments will be carried out with members of the general population to determine which psychological factors perpetuate dissociative experiences. Then, a psychological treatment which targets one or more of these factors will be developed and tested with a small group of people with psychosis and dissociation.

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

Exploring the mechanisms of centriole growth and ciliogenesis 30 Sep 2018

When cells divide, their genetic material is distributed between the new daughter cells. Problems at this stage can lead to genome instability, which may promote cancer. Centrioles (barrel-shaped structures in animal cells, surrounded by a layer of microtubules) organise cilia and centrosomes, the latter being the organelles that coordinate the mitotic spindle to pull the genetic material apart. Like the genetic material, centrioles must duplicate every cell cycle so each daughter cell inherits one centrosome. Consistently, the nascent centrioles grow until they reach the same length as the older centriole. I aim to gain insight into how this precise growth is achieved by studying CEP104, a protein implicated in centriole growth regulation. I will investigate the effect of Cep104 knockout on centriole growth in Drosophila melanogaster embryos. I will also study CEP104 dynamics in vivo using fluorescently tagged CEP104, and see how this is affected under different conditions and genetic backgrounds. This, together with interaction assays, will offer insight into the interactions occurring between centriolar proteins during centriole growth. Alongside this work, I hope to determine CEP104’s role in promoting cilia formation in quiescent cells, which represents an important switch between the centriole’s role in centrosome versus cilia organisation.

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

Planning meeting for Lancet Commission on Diagnosis 30 Sep 2018

The Lancet Commission on Diagnosis Phase 1 - Planning Meeting Following the publication of The Lancet Series on Pathology in Low and Middle Income countries in March, the Lancet asked me to lead a Lancet Commisison on Diagnosis (Pathology and Laboratory Medicine and Imaging). There will be two phases. The first will be a 1.5 day face-to-face meeting of a small interim executive group ( see other participants) to plan the first full meeting of the Commission. Phase II will be the rest of the three year Commission. The main tasks of Phase I will be; Identify/invite possible Commissioners ( around 20) of international stature with geographic diversity, expertise in the different disciplines, policy making, health systems development, technological innovation and education. Decide aims/objectives and agenda for the first full Commission meeting. Select the site and start the process of booking facitlities, arranging travel, etc. We wish to hold the Phase I Planning Meeting in mid October, probably in London. We estimate the costs as approximately £8000.

Amount: £8,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Autophagy in the interplay between haematopoiesis and the bone marrow niche 30 Sep 2018

Autophagy (greek ‘self-eating’) is a cellular recycling process, which can provide new building blocks and energy to cells. Immune cells require autophagy for their differentiation, maintenance and function. Hence, decreased autophagic flux, which occurs naturally during aging, results in diminished immune function. The effect of autophagy in immune cells is particularly apparent in immune cells that permanently live or are generated in the bone marrow (BM). We aim to understand how autophagy regulates the interplay of immune cells and the BM environment. First, we aim to deplete autophagy in hematopoietic stem cells using genetic models and assess the effects on supporting cells in the bone marrow. For this we will use global and bioinformatic tools to study the BM composition based on both, gene expression and metabolite production. Second, we aim to deplete autophagy from bone marrow adipocytes, a subset of cells known to be able to provide building blocks and metabolites such as fatty acids to surrounding cells. We will study normal hematopoiesis and long-lived immune responses in this new mouse model. Findings from this project will be key to identify better conditions for hematopoietic stem cell transplantations and counteract negative effects of aging including inflammation.

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

Mechanisms of DNA interstrand crosslink repair in humans. 10 Apr 2018

My research is focused on uncovering the molecular mechanisms of DNA interstrand crosslink (ICL) repair in humans. Disruption of the underlying DNA-repair pathway causes Fanconi Anemia (FA), with serious cancer susceptibility. Also, ICL-forming drugs are used therapeutically in non-FA cancer patients, however resistance is a major problem. Targeting the FA-pathway could allow clinicians to treat these patients. A key and fundamental event in the FA-pathway is the recruitment of repair proteins to ICLs. Specific and timely recruitment is essential for accurate repair. We have recently discovered proteins specifically detecting ICLs and we have obtained the cryo-EM structure of other ICL-repair proteins. My aim over the next five years is to advance the field further by uncovering mechanistically how repair factors are activated and recruited to ICLs at the single-molecule level. We will: 1) Dissect the mechanism of initial recruitment of repair factors to ICLs. 2) Uncover functions of identified proteins in FANCD2-complexes in ICL-repair. 3) Determine roles of novel phosphorylation sites on FANCD2/FANCI. 4) Elucidate mechanism of FANCD2/FANCI activation. Addressing these central questions will not only greatly advance our understanding of ICL-repair, but will also likely enhance our understanding of other DNA repair pathways utilizing analogous mechanisms.

Amount: £1,573,740
Funder: The Wellcome Trust
Recipient: University of Oxford

Structural and biophysical analysis of iRhoms, their domains and their binding partners 30 Sep 2018

A particular family of white blood cell called macrophages produce various molecules that trigger inflammation and initiate the immune response. One such molecule, called TNF-alpha, is a protein that is normally tethered to the surface of macrophages and needs to be cut free in order to function. The release of TNF-alpha at the surface is achieved by the activity of an enzyme called TACE, in a process that is aided by another protein called iRhom. Therefore iRhom and TACE play important roles in the initiation of inflammation, both in terms of response to infection/injury and in the more damaging cases of diseases such rheumatoid arthritis. This project involves investigating the interaction between mammalian iRhom and TACE at a molecular level. Mechanistic and structural knowledge of how these two proteins interact will help broaden the understanding of some of the mechanisms that initiates the immune system.

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

CHIM - Shigella sonnei in Vietnamese adults - Development funds 17 Nov 2017

Diarrhoea remains a major cause of childhood morbidity and mortality globally. The vast majority of the 2 billion annual diarrhoeal infections occur in low and middle-income countries (LMICs). Members of the genus Shigella are key agents of diarrhoea in LMICs, and S. sonnei is replacing S. flexneri as the predominant species globally. There is a necessity to improve our knowledge of S. sonnei infections in LMICs, with a specific requirement to better understand host-pathogen interactions and the natural history of disease in a setting where the organism is well understood, well described, and associated with a significant disease burden. Therefore, we aim to establish a Controlled Human Infection Model (CHIM) of S. sonnei diarrhoea in healthy Vietnamese adults. This is an innovative project will be the first CHIM study conducted at the Vietnam MOP. Therefore, it is imperative that the project is carefully designed in consultation with all relevant stakeholders. In order to ensure that the proposal is developed to the required standard in the timeframe available, I am requesting funds to employ an international postdoctoral assistant, with a background in microbiology and clinical research on a consultancy basis.

Amount: £21,120
Funder: The Wellcome Trust
Recipient: University of Oxford