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Results

Investigating the roles of Toxin/Antitoxin module in pathogenic Neisseria 04 Dec 2017

Pathogenic Neisseria species continue to cause harmful infections in humans. Neisseria meningitidis causes life threatening meningitis and septicaemia infections, particularly in infants, and Neisseria gonorrhoeae causes the sexually trasmitted infection gonorrhoea. There is an urgent need to further study these pathogens particularly N. gonorrhoeae as gonorrhoea cases are on the rise and it is increasingly in the news due to the sharp increase in cases with resistance to antibiotics, leading to the fear that gonorrhoea could soon become untreatable. We will investigate the role that toxin/antitoxin modules play in Neisseria biology. In other pathogens, these systems have been observed to include a toxin able to stall bacterial replication and an antitoxin that neutralises the toxin's activity. When under stress, the antitoxins are degraded leaving a free toxin to arrest bacterial growth. In this non-growing state bacteria are tolerant to antibiotic challenge. There is very little known about how the toxins of Neisseria function and what their role is in infections. This proposal will address this lack of knowledge by discovering the biological systems targeted by the toxins and assessing their effect on Neisseria metabolism.

Amount: £99,861
Funder: The Wellcome Trust
Recipient: University of Sussex

Recognition, activation and targeted degradation of protein kinases clients by the HSP90-molecular chaperone 10 Apr 2018

Many oncogenic protein kinases depend on interaction with the HSP90 molecular chaperone, mediated by the co-chaperone CDC37, for their cellular stability and oncogenic activity. Inhibition of HSP90's conformationally-coupled ATPase mechanism leads to the ubiqtuitylation and degradation of these protein kinase 'clients'. Consequently HSP90 is an important target for therapeutic intervention in cancer. Although there has been substantial progress in this field, important issues remain unresolved. In particular we wish to understand : How protein kinase clients are specifically and selectively recognised by the CDC37 co-chaperone, and recruited to HSP90 ? What structural and biochemical changes are elicited in the client protein by recruitment to HSP90 and by its conformationally-coupled ATPase cycle ? How dephosphorylation of CDC37 by the HSP90-targeted protein phosphatase PP5 regulates client protein release ? How protein kinase clients are targeted for proteasomal degradation when HSP90's ATPase is inhibited ? To address these questions we will use cryoelectron microscopy, X-ray crystallography, NMR spectroscopy, and a range of biochemical and biophysical approaches, to determine structures of key complexes along the pathway from initial client recognition to release or ubiquitylation, and define the structural and biochemical transitions that connect them.

Amount: £2,027,915
Funder: The Wellcome Trust
Recipient: University of Sussex

Alpha-GABa receptor modulators for the treatment of cognitive impairment associated with Huntington’s disease 01 Oct 2017

Huntington's disease is a fatal genetic disease characterised by a movement disorder that is accompanied by a decline in cognitive function and changes in mood and behaviour. The decline in cognitive function may precede the movement disorder by a decade or more and is a very important component of the functional disability associated with the disease. There is, however, no effective treatment for enhancing cognitive performance in Huntington's. Professor John Atack at the University of Sussex aims to identify novel drugs that can enhance cognitive performance in subjects with Huntington's disease to address a large unmet medical need.

Amount: £810,920
Funder: The Wellcome Trust
Recipient: University of Sussex

Open Access Award 2017/18 30 Sep 2018

Not available

Amount: £45,702
Funder: The Wellcome Trust
Recipient: University of Sussex

Enhancing electron microscopy facilities at the University of Sussex with High-Pressure Freezing technology 06 Jul 2017

We are requesting a high-pressure freezer (HPF) and freeze-substitution processor (FSP) at the University of Sussex to substantially enhance our transmission electron microscopy research and meet significant unmet demand. HPF/FSP is now the de facto standard for the highest-quality specimen fixation for ultrastructural work, offering key benefits for protein integrity, ultra-rapid controlled fixation, fluorescence preservation for correlative work and penetrative thick-sample fixation. The requested system includes modules for synchronizing optogenetic/electrical stimulation with freezing onset, offering revealing ‘snapshot’ views of rapid and dynamic events. Collectively, these advantages will open up major new directions for existing research programs within the School of Life Sciences, and wider afield. Planned research includes studies aimed at: defining synaptic vesicle recycling pathways in central and sensory terminals, revealing ultrastructural correlates of disease-related neuronal dysfunction, elucidating chromosomal breakage events during mitosis, investigating ultrastructural determinants of centrosome positioning, and characterizing protein organization in ionizing radiation-induced foci. The School has made major recent strategic investment in developing world-class electron microscopy facilities and the HPF/FSP will offer significant enhancements to this equipment for ultrastructural research. The system will be fully-integrated into the new purpose-built Life Sciences building (completion 2019-2020) ensuring its long-term sustainable use within a state-of-the-art dedicated Bio-Imaging centre.

Amount: £337,311
Funder: The Wellcome Trust
Recipient: University of Sussex

Institutional Strategic Support Fund 07 Sep 2016

Not available

Amount: £900,000
Funder: The Wellcome Trust
Recipient: University of Sussex

Global Atlas of Podoconiosis 22 Jun 2016

In 2011, podoconiosis was identified as one of the Neglected Tropical Diseases by the World Health Organization. Many questions remain, however, about the geographical distribution and burden of podoconiosis globally. These include; what is the global distribution of podoconiosis, what global burden does it impose, are factors associated with podoconiosis universal or country specific, and what is the cost of podoconiosis control and elimination? This fellowship will enable these questions to be answered. The proposed work will build upon a nationwide mapping technique which was applied in Ethiopia. First, I will test the universality of factors associated with podoconiosis by conducting a nationwide survey in Cameroon. Second, I will investigate the spatial distribution of podoconiosis globally by conducting surveys and applying geostatistical and boosted regression modeling. Third, I will quantify the population at risk globally and the number of people affected, using a Bayesian meta-regression method, DisMod-MR, employed by the Global Disease Burden studies, to estimate the disability adjusted life years (DALYs) attributable to podoconiosis. Fourth, using a micro-costing approach that allows adjustment for time-variant resource utilization and for heterogeneity, I will estimate the cost of control and elimination. Findings will directly inform the global control and elimination of podoconiosis.

Amount: £660,064
Funder: The Wellcome Trust
Recipient: University of Sussex

Spatial regulation of meiotic recombination 05 Apr 2016

Our goal is to understand the mechanisms regulating the spatial distribution of genetic recombination during meiosis—a specialised cell division responsible for genome haploidisation during gametogenesis. We recently demonstrated that the distribution of meiotic DNA breaks (DSBs)—the precursors of genetic recombination—is non-random, being regulated by the evolutionarily-conserved DNA damage response (DDR) checkpoint protein Tel1 (ATM in mammals). In this proposal we will build upon this ground-breaking work, to test the manner in which chromosome structure shapes the distribution of meiotic recombination. First, we will determine the genome-wide distribution of clustered DSBs that arises when Tel1 activity is absent, and determine the functional association of such sites with higher-order chromosome loop structures. Second, we will monitor the 3D organisation of meiotic chromosomes, and of loop subdomains, and relate this information, mechanistically, to the location and spatial distribution of recombination. Third, we will investigate Tel1-independent mechanisms of spatial regulation, specifically testing the hypothesis that chromatin loop "clustering" mediates local DSB suppression. In many organisms, including humans, control of the initiation and spatial distribution of recombination is critical to both reproductive and evolutionary success. Our proposed work programme will shed mechanistic insight into the regulation of this fundamental process.

Amount: £1,143,626
Funder: The Wellcome Trust
Recipient: University of Sussex
Amount: £2,026,044
Funder: The Wellcome Trust
Recipient: University of Sussex

Open access block grant 2016/17 30 Sep 2016

Not available

Amount: £27,001
Funder: The Wellcome Trust
Recipient: University of Sussex

Design and development of AMPA receptor modulators with a much improved safety profile as novel drugs for treating the cognitive dysfunction associated with schizophrenia and other CNS disorders 10 Dec 2015

Around 1% of the population will suffer from schizophrenia at some point in their life. Symptoms such as paranoia and/or hearing voices can be reasonably well treated by existing medications. However, these drugs have little effect on the other symptoms (lack of motivation and impaired social function) and impaired cognition, including difficulties with attention, memory and problem-solving that result in a “brain fog”. These largely untreated symptoms remain a huge barrier to the resumption of a fully functional, “normal” life for these individuals and are associated with an annual estimated cost in the UK alone of around £12 billion. Professor Simon Ward from the University of Sussex has received a Seeding Drug Discovery Award to identify and develop drug which is a selective modulator of the AMPA receptor which has the potential to provide an innovative new treatment for patients with schizophrenia. If successful the team expect to have a compound ready for clinical evaluation in just over three years time. Nerve cells (neurons) communicate with each other by releasing chemicals known as neurotransmitters that interact with proteins called receptors on adjacent neurons. Levels of the neurotransmitter glutamate, which is crucial for normal cognitive function, are altered in schizophrenia. A specific subtype of glutamate receptor, the AMPA receptor, is thought to be associated with cognition and therefore increasing AMPA receptor function should improve cognitive performance in schizophrenia and thereby addressing an unmet need and revolutionizing the functional outcome of this patient population.

Amount: £6,124,080
Funder: The Wellcome Trust
Recipient: University of Sussex

Wellcome Trust Engagement Fellowship 20 Jul 2016

Why is life in the first person? There is nothing more fundamental to the human condition than the question of consciousness, at once the most familiar and most mysterious aspect of our existence. Without consciousness there is simply nothing at all: no world, no self, nothing. People have wondered about consciousness since they’ve wondered about anything, but the relationship between conscious experience and biological wetware has remained perplexing, to scientists and clinicians, to philosophers and artists, indeed to everyone who has ever wondered at being at the centre of one’s own ‘inner universe’. At the same time, society is witnessing a vast increase in psychiatric and neurological illnesses – the edges of consciousness – which are poorly understood and inadequately treated. My vision is to combine pioneering research and public engagement (PE) to transform our understanding of the biological basis of consciousness in health and in illness, and in doing so, to reframe the way we – all of us – encounter being human. Following Copernicus and Darwin, deciphering the biological basis of consciousness will help us see ourselves as part of, and not apart from, the rest of nature. The scientific, medical, and cultural ramifications of these developments are dramatic, even extending beyond the human condition to change the way we see non-human animals and future intelligent machinery. The science is already happening, with my research group among the pioneers. I will ensure the wider public not only comes along for the ride, but also becomes actively involved in shaping the research we do and the conclusions we draw. We are all conscious, so this matters to everyone. I see a unique opportunity in combining my distinctively broad range of influential research with my already impactful PE activities. Presently, with few exceptions, most high-level PE comes from individuals dedicated to science communication, while most high-level scientists necessarily focus on research with PE activities treated as secondary. My vision is for a distinctive brand of high-quality PE made possible by my being simultaneously active at the highest levels of the relevant research. I am uniquely qualified to achieve and sustain this vision. I have published influential papers across a very broad range of topics in consciousness science (>100 papers published, h-index 40, see attached CV), and as editor of the academic journal Neuroscience of Consciousness I enjoy a broad field overview. In addition, I have already demonstrated a strong PE track record across many domains (see supplementary information, SI). These contributions provide the ideal platform from which I can realize my vision of research-led PE to transform our scientific and public understanding of the biology of consciousness. My vision encompasses informing and exciting the public about consciousness science through a variety of formats, engaging with clinical practitioners across psychiatry and neurology to develop a greater mutual appreciation for how consciousness science can inform diagnosis and treatment, and ensuring that consciousness science as a discipline becomes increasingly established as a central field within the mind and brain sciences.

Amount: £167,726
Funder: The Wellcome Trust
Recipient: University of Sussex

Bacterial RNA profiling to predict tuberculosis treatment failure 15 Aug 2016

At present there is no way of accurately predicting tuberculosis (TB) treatment failure and relapse to active disease. This results in the over-treatment of many patients, who might safely stop the toxic six-month therapy earlier, and necessitates lengthy and costly clinical trials to assess new therapies, thus creating a bottleneck to progress. This innovative project will test whether the transcriptional response of TB isolated from patient sputa during the first few days of treatment will predict relapse months later. Building on the applicant’s recent study demonstrating that sputa TB mRNA signatures differ between patients and reflect clinical/microbiological measures of disease, this proof-of-concept prospective patient study will for the first time define markers of relapse. TB RNA from patient sputa will be assayed by targeted and genome-wide profiling techniques at diagnosis and at multiple timepoints after the start of drug therapy. RNA yields and gene expression signatures will be analysed to determine key methodological parameters concerning the collection and detection of sputa TB RNA and to assess applicability in the UK and Cameroon. Finally, TB mRNA signatures from relapse and successfully-treated patients will be compared using this novel discovery approach to identify biomarkers that predict relapse, transforming the management of TB.

Amount: £99,201
Funder: The Wellcome Trust
Recipient: University of Sussex

ASTRODEM: Using astrophysics to close the “diagnosis gap” for dementia in UK general practice 08 Apr 2016

Dementia is one of the greatest public health challenges of our era. Timely diagnosis allows patients to benefit from current therapies, plan for the future, and maximise their quality of life. However, there is a "diagnosis gap" in UK general practice, with less than two-thirds of expected patients receiving a dementia diagnosis. Increasing diagnosis rates is a strategic aim of the UK government and NHS. We aim to close this diagnosis gap in a novel collaboration between primary care epidemiology and astrophysics. We will use a very large set of UK general practice electronic patient records (96,000 patients; 50% with dementia) spanning up to 10 years per patient. We will use a probabilistic programming framework to apply statistical techniques to model dementia onset in this cohort, allowing for the inherent variability and duration of disease development. To achieve a clinically valuable model, these multi-dimensional data will require sophisticated analysis techniques that are not currently available in medical statistics and epidemiology, but which astrophysicists use daily. Our goal is to develop a statistical model to predict risk of dementia from patients' general practice records, which will help GPs and other NHS bodies better estimate and identify cases in UK general practice.

Amount: £94,008
Funder: The Wellcome Trust
Recipient: University of Sussex

Alpha-GABa receptor modulators for the treatment of cognitive impairment associated with Huntington’s disease 22 Oct 2015

Huntington's disease (HD) is a fatal genetic disease characterised by a movement disorder that is accompanied by a decline in cognitive function and changes in mood and behaviour. The decline in cognitive function may precede the movement disorder by a decade or more and is a very important component of the functional disability associated with HD. There is, however, no effective treatment for enhancing cognitive performance in HD. The Professor John Atack from the University of Sussex aims to identify novel drugs that can enhance cognitive performance in subjects with HD and thereby address a large unmet medical need.

Amount: £1,478,688
Funder: The Wellcome Trust
Recipient: University of Sussex

Design and development of AMPA receptor modulators with a much improved safety profile as novel drugs for treating the cognitive dysfunction associated with schizophrenia and other CNS disorders 30 Jul 2016

Around 1% of the population will suffer from schizophrenia at some point in their life. Symptoms such as paranoia and/or hearing voices can be reasonably well treated by existing medications. However, these drugs have little effect on the other symptoms (lack of motivation and impaired social function) and impaired cognition, including difficulties with attention, memory and problem-solving that result in a “brain fog”. These largely untreated symptoms remain a huge barrier to the resumption of a fully functional, “normal” life for these individuals and are associated with an annual estimated cost in the UK alone of around £12 billion. Professor Simon Ward from the University of Sussex has received a Seeding Drug Discovery Award to identify and develop drug which is a selective modulator of the AMPA receptor which has the potential to provide an innovative new treatment for patients with schizophrenia. If successful the team expect to have a compound ready for clinical evaluation in just over three years time. Nerve cells (neurons) communicate with each other by releasing chemicals known as neurotransmitters that interact with proteins called receptors on adjacent neurons. Levels of the neurotransmitter glutamate, which is crucial for normal cognitive function, are altered in schizophrenia. A specific subtype of glutamate receptor, the AMPA receptor, is thought to be associated with cognition and therefore increasing AMPA receptor function should improve cognitive performance in schizophrenia and thereby addressing an unmet need and revolutionizing the functional outcome of this patient population.

Amount: £992,390
Funder: The Wellcome Trust
Recipient: University of Sussex

Expression and purification of ApolipoproteinE4 - A potential target for Alzheimer's disease therapeutics 01 Apr 2016

The purpose of my project will be to express and purify the human recombinant ApoE4 isoform as the basis for conducting subsequent structural analysis and small molecule screening in an early-stage drug discovery project. In the first instance, I will attempt to reproduce previously published data with so-called "structural correctors" that convert the morphology of the "bad" ApoE4 isoform into the more benign "good" ApoE3 isoform. More specifically my aims will be: 1. Small-scale expression tests of human ApoE4 cDNA in various standard strains of bacteria (E. coli) 2. Large-scale (2-5L) expression of ApoE4 under optimal conditions identified in Step 1. 3. Isolation and purification of ApoE4 using affinity, size and/or ion exchange chromatography and fast-protein liquid chromatography (FPLC) Stretch objectives (if all goes well) include: 4. Crystallography trials and thereafter X-ray crystallography 5. Development of an ApoE4 strucutural conformation assay using a previously-published fluorescence resonance energy transfer (FRET) assay

Amount: £2,000
Funder: The Wellcome Trust
Recipient: University of Sussex

Cryo-EM of multiprotein complexes 09 Feb 2015

The Hsp90 molecular chaperone plays an essential role in the stabilisation andactivation of a wide range of client' proteins, including some of the most important proteins required for cell maintenance and regulation in eukaryotic organisms from yeast to humans. Hsp90 itself is regulated by a plethora of co-chaperone proteins that modulate its essential ATPase coupled conformational cycle, and/or act as adaptors facilitating recruitment of specific client proteins to the Hsp90 machinery. Involvement of Hsp90-dependent clients in the development and progression of cancer, has led to enormous interest in Hsp90 as a drug target, and an emerging realisation of Hsp90 involvement in viral and and parasitic infections, suggests that Hsp90 is important in many other diseases. Although much of the biochemistry of the Hsp90 system has been unravelled in recent years, central questions of Hsp90 biology remain unanswered. To address this, we propose to define at the structural level the molecular mechanisms by which the Hsp90 molecular chaperone system contributes to the activation, stabilization and regulation of its selected client' proteins in eukaryotic cells

Amount: £274,320
Funder: The Wellcome Trust
Recipient: University of Sussex

Institutional Strategic Support Fund Phase2 FY2014/16 27 Oct 2014

The Institutional Strategic Support Fund (ISSF) is co-funded by The Wellcome Trust and strategic support from the University for the Genome Damage and Stability Centre and the Translational Drug Discovery Group. The ISSF supports our Vision for Translational Biomedical Research in three main ways : Translational Platform: supporting the establishment and operation of the multidisciplinary early-stage translational platform, by co-funding core posts and consumables. Pilot Fund: providing an opportunistic pilot fund to support exploratory studies to enable new targets arising from discovery science projects across the University and Medical School, to access key resources required to bridge from discovery to translational science to enable both strong clinical target validation and entry into the drug discovery pipeline. Public Engagement : supporting Public Engagement and Widening Participation activities to inform and educate the public on the ways that we are translating basic discovery research to real impact in the diagnosis and treatment of major human diseases, and to encourage and support students from less privileged backgrounds to enter careers in translational science.

Amount: £600,000
Funder: The Wellcome Trust
Recipient: University of Sussex