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Results

Serine ADP-ribosylation in genome stability and human disease 10 Apr 2018

ADP-ribosylation (ADPr) is a post-translational modification (PTM) of proteins, synthesised by the poly(ADP-ribose) polymerase (PARP) family of enzymes. Through the modification of a variety of mediator/effector proteins, PARPs control cellular processes that are critical for genome stability, including DNA repair, regulation of chromatin structure, transcription, apoptosis and mitosis. However, the proteins involved in these pathways and their mechanisms of regulation remain poorly understood. Recently, we identified ADPr on serine residues in proteins (Ser-ADPr) as a previously unknown PTM. We showed that Ser-ADPr synthesis is dependent on histone PARylation factor 1 (HPF1), a recently identified specificity factor and interactor of DNA repair PARPs - PARP1 and PARP2. We further showed that Ser-ADPr specifically targets proteins involved in the maintenance of genome stability. Finally, we also revealed that a hydrolase called ARH3 acts as specific enzyme for a timely reversal of Ser-ADPr. Our first goal of this project is to use biochemical and structural approaches to understand the exact molecular mechanism by which HPF1 and ARH3 work in the synthesis/removal of Ser-ADPr. Our second goal is to define the physiological processes controlled by Ser-ADPr and to understand how these processes are regulated in cells, using cell biology approaches and animal models.

Amount: £2,074,702
Funder: The Wellcome Trust
Recipient: University of Oxford

Expanding the Inventory Records and Online Profile of Early Modern Medical Books at the Science Museum 18 Jun 2018

The short-term goal of my six-month project is to create a new inventory of the Science Museum’s 158 pre-1800 medical books which would contain more up-to-date, detailed information about the contents, physical format and publication circumstances of the predominantly Latin and English codices. I also intend to explore and document links between the books and the museum’s large collection of medical objects. My project will also contribute to the long-term goal of making the books more accessible by the museum’s online search platforms. Consequently, part of my project may involve developing contextual materials to accompany the books, such as more in-depth, accessible information about the authors, the broader concepts they are engaging with, and their place within the history of medicine. I would also be keen, if possible, to increase the online presence of these books by writing a short, informal and engaging article aimed at the general public for the Science Museum Blog, or a more formal article on the process of cataloguing them for the Science Museum Group Journal.

Amount: £13,005
Funder: The Wellcome Trust
Recipient: University of Oxford

Modelling the impact of poor quality antimicrobials on patient outcome and drug resistance – a pilot study to inform policy in the absence of empirical data 30 Sep 2017

Antimicrobial resistance (AMR) is an increasingly serious and pressing global public health problem. Poor antimicrobial quality is increasingly realised as an important rectifiable impediment to global public health. There has been little discussion or evidence as to its comparative importance, in relation to other drivers such as poor prescribing and adherence, for both poor patient outcomes and AMR. In the absence of field data on the relationship between AMR and antimicrobial quality, mathematical modelling based on pharmacokinetic-pharmacodynamic relationships and rates of genetic change provides estimates which can be used to predict outcomes and inform policy. We propose a two phase modelling approach examining how poor quality essential medicines may affect patient outcomes and resistance selection and spread, modelling in Phase 1 antimalarials and in Phase 2 anti-tuberculosis and anti-hepatitis C medicines. This pilot project will build on the existing Wellcome investment in the Mahidol Oxford Research Unit (MORU) Network (though core funding) and the Infectious Diseases Data Observatory (through the MAPQAMP Biomedical Resources grant and core funding) for modelling, PK/PD and medicine quality resources and skills. The growing interest in medicine quality by nations and international organisations and the invitation by the WHO Member State Mechanism (on medicine quality) to the IDDO/MORU Medicine Quality Group to be a stakeholder, facilitates synergistic discussions with multiple partners and nations. We are also discussing expanding our collaboration with the United States Pharmacopeia PQM program on medicine quality & AMR. We are organising the first Conference on Medicine Quality & Public Health for September 2018 and we intend that the initial results from this work would be presented at this meeting. This project will therefore give the first objective evidence, rather than opinion, on the importance, or otherwise, of medicine quality on patient outcome and AMR, in comparison to poor adherence and poor prescribing. It will link in extremely well with the diverse activities of the MORU Network, IDDO, WHO, USP and diverse other stakeholders and be opportune for influencing policy for both medicine quality and AMR. This project will be linked to the parallel project proposed to Wellcome by Dr Elizabeth Pisani on ‘Understanding the political barriers to tackling sub-standard and falsified medicines’.

Amount: £99,994
Funder: The Wellcome Trust
Recipient: University of Oxford

Understanding the functional role of GABA across the human motor network 05 Dec 2016

Understanding the functional role of GABA across the human motor network

Amount: £214,011
Funder: The Wellcome Trust
Recipient: University of Oxford

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

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

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

Structural studies of the host-parasite interactions at the heart of malaria pathogenicity 05 Apr 2018

Our proposed activities consist of two major strands. Firstly we wish to take our research on tour, developing a high quality interactive stall which will allow us to present our findings to those who visit science fairs. We have secured a place at the Royal Society Summer Science Exhibition in July 2018, as the first outing for our display and this provides the deadline by which we must have the stall in place. As this is one of the UK’s premier science festival, visited by ~13,000 people each year, this is a great opportunity to meet people and to share our research. We will also ensure that our stand is fully updateable in content – for example using interactive screens which can be altered over time. We will next present at the Oxford Science Festival in 2019 and 2020, at which the Biochemistry Department has committed space. We will also apply to present at another major science festival as soon as applications open (i.e. Cheltenham and Edinburgh) in each of 2019 and 2020. This will be supported by digital content, including a ~2 minute video which will describe our approach towards rational malaria vaccine design and will be posted on Youtube. We will also develop an interactive vaccine game in which players can allocate health budgets and see the effect on malaria prevalence. Together with informative content about our research, these will widen the accessibility of our research.

Amount: £49,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Understanding unconventional kinetoplastid kinetochores in Trypanosoma brucei 10 Apr 2018

I am interested in understanding the mechanism of how eukaryotic cells inherit their genetic material at each round of cell division. I have been studying the kinetochore, the macromolecular protein complex that drives chromosome segregation. Although it was widely believed that the structural core of kinetochores would be composed of proteins that are conserved in all eukaryotes, I discovered an unconventional class of kinetochore proteins (KKT1–20) in Trypanosoma brucei, an evolutionarily-divergent kinetoplastid parasite. My current goal is to understand how they carry out conserved kinetochore functions such as binding to DNA and microtubules. Based on preliminary data, I propose that two homologous protein kinases KKT2 and KKT3 lie at the base of the kinetoplastid kinetochore. I will aim to understand how these proteins localize specifically at the centromeric DNA using a variety of approaches. I will also characterize the KKT4 protein to reveal the mechanism of microtubule interaction. To understand the design principle of kinetoplastid kinetochores, I will reconstitute and characterize kinetochore subcomplexes. Finally, I will examine how the evolutionarily-conserved Aurora B kinase regulates the function of unconventional kinetoplastid kinetochores.

Amount: £1,890,493
Funder: The Wellcome Trust
Recipient: University of Oxford

An exploration of the role L-type calcium channels in mood, cognition and sleep. 30 Sep 2018

I plan to explore the effect of nicardipine, a brain-penetrant calcium channel antagonist, on mood instability and its cognitive/neural correlates. This research (carried out within the Collaborative Oxford Network for Bipolar Research to Improve Outcomes [CONBRIO]) has a number of goals. In addition to studying effects of L-type calcium channel (LTCC) antagonism on mood instability, I will investigate effects on sleep/cognition, and on brain activity measured by functional imaging. Rationale is provided by (a) considerable evidence for calcium signalling abnormalities in bipolar, (b) current mood stabilisers correct some of these abnormalities, (c) calcium channel genes contribute to the basis of bipolar as well as to memory/sleep. Moreover, LTCC antagonists are used for heart disease and available for experimental studies; there have also been early studies in bipolar disorder but no robust results. I will study volunteers screened for high mood instability and risk CACNA1C genotype, and assess mood, sleep, cognition, and neural activity, before and after randomisation to nicardipine or placebo. Results will inform whether trials of LTCC antagonists for bipolar disorder are indicated, and their likely efficacy/tolerability. I will learn to conduct a randomised trial, principles of experimental medicine, and aspects of cognition, circadian-biology, and functional brain imaging.

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

The Effect of Priorizing Information in Working Memory on Later Behavioural Interference 31 May 2018

This experiment will investigate how prioritised information is represented in working memory (WM) through looking at the serial dependence effect. Myers and colleagues (2017) have suggested that items which are prioritised in WM are transformed into action-ready representations. Therefore, the theory predicts that the difference between prioritised and non-prioritised representations in WM will be reflected in behavioural findings. The serial dependence effect occurs when visual information from the recent past biases perception and behaviour at the present moment (Fischer & Whitney, 2014). If prioritised WM items were stored in an action-oriented format, we predict it will show these interference effects in behaviour more than non-prioritised information. By using an orientation adjustment paradigm, we will measure the serial dependence effect for prioritised WM items (which have been retro-cued) versus non-prioritised WM items. In addition, we will vary the type of testing (forced choice versus free recall), predicting that more interference will occur when the tests are the same than when different, due to the action-based nature of the WM representation. Initially we will use behavioural measures (reaction times) to measure the interference effects, extending to EEG to measure neural evidence for the carry-over effects.

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

Role of lipid-reactive T cells in skin homeostasis and disease 28 Nov 2017

Immunological mechanisms underlying the maintenance and function of human skin during homeostasis and inflammation remain poorly understood. The majority of our existing knowledge of human cutaneous T cell immunology is based on the study of peptide-specific T cell responses. However, recently it has become clear that T cell responses to lipid-based antigens make major contributions to normal physiology and inflammation in the skin. Specifically, the Major Histocompatibility Complex (MHC) class I-like molecule, CD1a, is highly expressed in human skin. Through collaborative studies, we have recently shown CD1a is able to present lipid antigens to skin T cells, contributing to the inflammatory skin response. The timing is therefore now ideal to address the underlying mechanisms in order to inform new approaches to treatment. In this multinational collaboration, with each principal investigator bringing complementary expertise, reagents and/or cohorts, we aim to investigate the role of lipids in human skin-based immunity. Our interdisciplinary approach will encompass lipidomics, chemistry, clinical dermatology, cellular immunology, and structural biology to identify and characterise the key parameters that define skin-based immunity to lipids. Such information will directly inform disease mechanisms and translational studies aimed at treating inflammatory skin diseases.

Amount: £3,000,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Establishing a Dengue Controlled Human Infection Model in Viet Nam 12 Mar 2018

Dengue is a mosquito-borne viral infection of major global significance. Millions of infections occur annually encompassing a wide clinical spectrum from inapparent infection to severe and fatal disease. Infection can be caused by any of four related serotypes but second infections with a different serotype are more likely to be associated with severity than primary infections. Although the first dengue vaccine was recently licensed, efficacy was only moderate despite demonstration of neutralising antibody responses to all serotypes, and there are now major safety concerns regarding priming of naïve vaccinees for severe disease later. To evaluate alternative vaccine candidates, NIAID has identified two attenuated challenge viruses with excellent safety profiles in dengue controlled human infection models (Dengue-CHIM) in US adults. We plan to collaborate with this experienced group to establish a similar Dengue-CHIM in Vietnam. However, since this is the first application in an endemic setting and no legal/regulatory framework exists, we propose an initial phase focused on bioethics/stakeholder engagement to develop a suitable regulatory framework, before moving forward to explore crucial research questions. An endemic setting Dengue-CHIM has great potential to advance dengue vaccine development and address the role of dengue immunity in the protection and pathogenesis of natural infection.

Amount: £802,357
Funder: The Wellcome Trust
Recipient: University of Oxford

Accessing the Druggable Genetic Programs Governed by Mammalian bHLH-PAS Transcription Factors 10 Apr 2018

We have recently projected that the human bHLH-PAS proteins form a class of transcription factors with great therapeutic promise, and propose to subject this family to in-depth chemical and functional explorations. The sixteen members of this family are functionally non-redundant and have genetic links to cancers, metabolic syndromes, inflammatory diseases, and psychiatric conditions. They share common architectural features that include a conserved DNA-binding domain and dual PAS domains. Our specific aims are: 1. Identify chemical ligands for members of the human bHLH-PAS family. 2. Determine the ligand-dependent genomic signatures and cellular pathways governed by family members. 3. Probe the mechanisms by which chemical ligands manifest their activities through this family. These studies allow us to transition from having visualized their ligand binding properties to employing chemical tools for interrogating and manipulating their functional activities as transcription factors.

Amount: £2,161,828
Funder: The Wellcome Trust
Recipient: University of Oxford

Medicine Quality and Public Health Conference 2018 30 Sep 2018

Globally, medicine regulatory authorities, research groups, international organisations, law enforcement agencies and other key stakeholders, including the pharmaceutical industry, are trying to keep patients safe and ensure that the benefits of modern medicine are delivered to patients. However, organisations working in this field tend to be fragmented with the wide diversity of professionals required to tackle this important issue, from chemists to lawyers, rarely discussing solutions together. Indeed, there has never been an opportunity for the diverse stakeholders involved in medicine quality and drug regulation to come together – within the framework of a specific academic conference – to share ideas and expertise, and to outline the coordinated steps that need to be taken to tackle the problem on an international scale. Drawing on the achievements of our successful, annual, multidisciplinary course on the Quality of Medical Products & Public Health at the London School of Hygiene & Tropical Medicine and Boston University, we are organising the first-ever dedicated academic and programmatic conference on Medicine Quality and Public Health. Wellcome is supporting the attendance of 10 participants from LMICs.

Amount: £24,000
Funder: The Wellcome Trust
Recipient: University of Oxford

STRatifying Antihypertensive Treatments In multi-morbid hypertensives For personalised management of Blood Pressure (STRATIFY-BP) 06 Jun 2018

Polypharmacy (five or more prescribed medications) is common in older people and is associated with an increased risk of adverse drug reactions. Preventative medications, such as those used to manage blood pressure and cholesterol, are common in polypharmacy and often require large numbers of people to be treated to prevent a small number of cardiovascular disease events. This leaves many individuals on drugs of little benefit, some of whom may be susceptible to side effects such as falls, kidney problems and muscle pain. As patients get older, the risks and benefits of their treatments may change, but doctors and patients have little information to inform their understanding of when this might happen. This proposal will use electronic health records with prediction modelling, causal inference and systematic review methods to establish the strength of association between antihypertensive therapy and side effects and build calculators which predict the likelihood of adverse events. These will be used to develop decision tools which predict an individual’s likelihood of benefit and harm from taking therapy. This approach will be applied to other preventative treatment areas and the resulting tools will help patients and doctors to make better informed decisions about starting or continuing these drugs.

Amount: £738,449
Funder: The Wellcome Trust
Recipient: University of Oxford

Timestamping Integrative Approach to Understand Secondary Envelopment of Human Cytomegalovirus 28 Nov 2017

The mechanisms facilitating the assembly of Human cytomegalovirus (HCMV) in the cytoplasm of infected cells, a complex process termed ‘secondary envelopment’, are poorly understood. Our goal is to identify in-situ the identity, position, and interactions of all the essential proteins involved in this critical stage of the viral ‘lifecycle’. Despite decades of research, it has been difficult to dissect the complexity of secondary envelopment, as bulk assays only show ensemble averages of populations of viral particles. To study these intermediates that are formed when cytoplasmic capsids acquire tegument proteins and their envelope membrane, we will develop a novel approach that separates these intermediates in time and space. We will provide their spatio-temporal models by integrating complementary cutting-edge techniques and expertise within this collaboration, including flow-virometry, correlative (fluorescence and electron cryo) microscopy, crosslinking and ion-mobility mass spectrometry-based proteomics, and computational modelling. Specifically, we aim to: -Identify key players in tegument assembly on capsids/membranes. -Elucidate the order and spatial organisation of tegument assembly. -Validate the interactions in vivo and analyse capsid tegumentation in vitro. -Integrate the information into a spatiotemporal model. This will significantly improve our understanding of herpesvirus assembly in general, a crucial step towards identifying new therapeutic targets.

Amount: £742,082
Funder: The Wellcome Trust
Recipient: University of Oxford