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Results

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

Institutional Strategic Support Fund 07 Sep 2016

Not available

Amount: £900,000
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

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

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

Have We Become Too Ethical? Managing vulnerability in social science research on health. 31 Mar 2015

Over the last decades the social sciences have adopted a model of ethical review based on the medical sciences. Questions have been raised about the appropriateness of a one-size-fits-all approach to ethical review in qualitative health research and particularly where vulnerable and hard-to-reach groups are involved. Our aim is to identify systematically the issues that underpin these concerns and examine how, through dialogue across health-related disciplines, new approaches might be deve loped to ensure better protection of subjects and better qualitative health research. We intend to accomplish this through a symposium, which will engage stake-holder communities (approx. 120 persons) and a small colloquium of experts from a range of disciplines gathered to consolidate outputs from the symposium (approx. 15 persons). We expect to explore three key areas (contextual factors in ethical review; Competence of reviewers; and informed consent) in both ethical review in the West a nd in international collaborations, where review systems and ethical issues often clash. The planned outputs comprise a special edition of a high profile journal with an introduction based on iterative reflection on the colloquium, and a briefing for use in health-related research among vulnerable populations and ethics committees.

Amount: £9,450
Funder: The Wellcome Trust
Recipient: University of Sussex

Open access publishing costs 2014/15. 15 Sep 2014

Not available

Amount: £21,256
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 disordersAround 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) an 24 Oct 2013

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: £1,944,086
Funder: The Wellcome Trust
Recipient: University of Sussex

Molecular basis of inheritable DNA lesions on genome transformation. 04 Jun 2014

The continuity of life requires the accurate inheritance and maintenance of genetic information. To preserve genome integrity, cells have evolved an efficient DNA damage responses to rapidly detect and repair DNA lesions. It is believed that unrepaired DNA damages, especially double-stranded breaks, are prone to initiate illegitimate genomic rearrangements and hence cause genome instability. Interestingly, recent research demonstrates that replication stress, which can cause incomplete replicati on of a genome, not only leads to the bridging of sister chromatids but also that its resolution results in the formation of persistent DNA lesions in succeeding daughter cells. Since replication stress is commonly found in cells with viral infection, in damaged tissues and, crucially, in pre-neoplastic and malignant tissues, I propose that inheritance of replication stress-induced DNA lesions is one of the primary causes of genome instability. In this research proposal my goal is to elucidate t he mechanism of genome rearrangements by understanding the molecular effects of inheritable DNA lesions on genome integrity. I aim to reveal the nature of, and the repair/protection mechanisms that respond to, inherited lesions. Crucially, I will explore their impacts on the maintenance of genome organization, integrity and their effects on cellular functions.

Amount: £982,479
Funder: The Wellcome Trust
Recipient: University of Sussex

High-throughput identification of small ORFs 06 Sep 2012

We have characterised a non-canonical gene, tarsal-less (tal). Tal is polycistronic and only contains small Open Reading Frames (smORFs) producing peptides as small as 11 amino-acids. These peptides function as a cell signal controlling gene expression and actin-mediated cell shape changes. I plan to ascertain the mechanisms for diffusion of these peptides and transmission of their signal by: A1) Investigating the mechanism of tal uptake in a cell culture assay; A2) Organising the proteins t hat bind tal (identified candidates and new ones to be searched for) in a pathway for the transmission of the signal; A3) Clarify the mechanism for tal-dependent transcriptional control; A3) Finding out how tal affects actin cytoskeleton. I also plan to search for more genes containing only smORFs in flies and other species, and to characterise a sample that will prove their existence as a class, and their general features, by: B1) searching for homologues of tal in distant species B2) characterising putative smORF genes we have already identified, to corroborate that their function is mediated by the small peptides they encode, and to obtain further information on their general structure and sequence signatures B3) searching for further smORF genes in flies, and finally in vertebrates

Amount: £107,282
Funder: The Wellcome Trust
Recipient: University of Sussex

Randomised controlled trial of podoconiosis treatment in northern Ethiopia 06 Jun 2012

The overall research objective of this project is to test the effectiveness of lymphoedema management in podoconiosispatients. At present, treatment of podoconiosis lymphoedema is not routinely provided by government services anywhere inthe world. In Ethiopia, where 1 million patients are estimated to live, non-government groups have developed simple,locally-appropriate treatment based on foot hygiene, emollients, bandaging, exercises to improve lymph drainage, and useof socks and shoes. Although one small proof-of-concept study suggests effectiveness of this treatment in relation toimprovement in outcomes such as leg circumference, stage of disease and quality of life, more rigorous testing isnecessary before treatment is extended within Ethiopia and to other podoconiosis-endemic countries like Cameroon, Rwanda, Uganda and Tanzania.The more detailed objectives are -1. To test whether podoconiosis lymphoedema treatment improves clinical outcomes, including decreased frequency ofacute dermatolymphangioadenitis, reduced disease stage, reduced lower leg circumference and prevalence of interdigitalentry lesions (macerations facilitating entry to micro-organisms);2. To test whether podoconiosis lymphoedema treatment improves quality of life outcomes and perceived stigma;3. To assess whether an 'intensive' model of delivery is more effective than a 'standard' model;4. To investigate whether podoconiosis lymphoedema treatment is cost-effective and has other benefits including increasedschool attendance.This will be achieved by conducting a pragmatic, single-blind randomised controlled trial with three intervention 'arms' thatwill compare two models of podoconiosis lymphoedema management in the community with delayed treatment (as control).Nine hundred adult (aged at least 16 years) podoconiosis patients located in independent households will be randomised,300 to each arm. Twenty community project assistants will support twice-weekly treatment at community sites, and tenindependent data collectors will make monthly follow-up visits. The principal analyses will be conducted at 6 and 12 monthsof follow-up.In common with many other research projects completed by our group, the results of this trial will be rapidly disseminatedto groups positioned to act on them, including Regional and District Health Bureaux, non-government organizations andpatient associations (see Communications Plan and Impact Summary). The other vital component of this trial is thetraining and capacity building it will provide, and the objectives in these areas are -5. To develop Clinical Trials capacity in Ethiopia through training and expertise-sharing by staff of the Kilifi Clinical TrialsFacility, a group with extensive experience of clinical trials support in East Africa;6. To provide high-quality supervised post-doctoral opportunities resulting in international publications for two outstandingEthiopian researchers

Amount: £150,902
Funder: The Wellcome Trust
Recipient: University of Sussex

Biomedical Vacation Scholarship. 20 May 2011

Not available

Amount: £1,440
Funder: The Wellcome Trust
Recipient: University of Sussex

Functional interplay between Epstein-Barr virus and the 53BP1/ATM DNA damage response pathway during viral replication. 02 Oct 2008

Epstein-Barr virus (EBV, HHV4) is a human gamma herpes virus that poses major clinical problems worldwide. Activating viral replication in EBV positive tumour cells enhances the host immune response to the virally infected cell; this can be of therapeutic value. A multifunctional viral protein, Zta, is critical for initiating viral replication. Delineating the molecular mechanisms of action of Zta and its interactions with host proteins will greatly increase our understanding of the basic mechan isms used by EBV to replicate and may suggest future avenues to modulate Zta function in therapeutic settings. EBV interacts with the DNA damage response (DDR) pathway through Zta: it interacts with the DDR protein 53BP1 directly and a Zta-associated viral protein kinase directs the phosphorylation of H2AX. Furthermore, ATM is activated during EBV replication and contributes to viral replication. Here we will identify the steps of EBV genome replication that are influenced by DDR activation, focusing on the chromatin environment around the origin of lytic replication and the generation of linear DNA genomes from the concatameric replication product. Furthermore, we will fully characterise the Zta/53BP1 complex during replication and identify the contribution of viral protein kinase to functional modulation of components of the complex.

Amount: £281,251
Funder: The Wellcome Trust
Recipient: University of Sussex

The ergonomics of electronic patient records: an interdisciplinary development of methodologies for understanding and exploiting free text to enhance the utility of primary care electronic patient records. 16 Jul 2008

Electronic patient records contain a mixture of coded information and free text. We will develop generalisable methods for the identification and interrogation of potentially important data concealed in free text, use the results to enhance coded data, and evaluate the utility of this approach. Through user centred methods, we will explore what influences clinicians in the balance between recording free text vs using standard codes (e.g. 002.23 Appendicectomy), and how information needs to b e stored for it to be useful to and retrievable by clinicians. Natural Language Processing (NLP) will be used to search the free text of large quantities of anonymised free text patient records, and to enhance coded data with pseudo-codes. Statistical methods will be used to explore the impact of integrating the additional information on (a) prevalence estimates (rheumatoid arthritis), and (b) estimates of dates of first relevant presentation (ovarian cancer). A visualization tool for the int egrated graphical display of coded and NLP generated data will be developed. It will be used to validate the novel data through clinician and researcher review, and thus to explore the value of these techniques in improving the quality and accessibility of information in electronic patient records.

Amount: £672,034
Funder: The Wellcome Trust
Recipient: University of Sussex

Investigating the dynamics of vesicle pool traffic in hippocampal synapses. 11 Feb 2008

Hippocampal synapses are now known to trade vesicles constitutively via an extrasynaptic mobile vesicle pool. This proposal will examine the regulation of this process in supporting the maintenance of synaptic structures, and examine whether vesicle trading can be utilized in a dynamic, activity-dependent manner to modulate synaptic efficacy. Vesicles will be labelled using GFP-based, photoswitchable, and activity-dependent fluorescent probes, and import/export dynamics examined using localized photobleaching/photoswitching techniques. Experiments will characterize cellular/molecular factors contributing to constitutive vesicle sharing under steady-state conditions. Activity-dependence of vesicle exchange will be tested by combining imaging with global or localized synapse-specific stimulation. These approaches will also be used to evoke forms of LTP-like long-term plasticity to test whether presynaptic vesicle pools locally recruit vesicles to undergo long-term remodelling, or build n ew functional release sites. The detailed changes associated with activity-dependent remodelling will also be examined by correlative fluorescence-ultrastructural analysis. Experiments will be performed in culture, but also in acute slices to establish the functional relevance of this process in native tissue. With these direct indices of presynaptic function, targeted at individual synapses and visualized down to their participating vesicle pools, this study should reveal important new insights into vesicle dynamics associated with presynaptic regulation and modulation.

Amount: £271,228
Funder: The Wellcome Trust
Recipient: University of Sussex

Value in People award. 18 Jul 2007

Not available

Amount: £150,000
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