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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

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

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

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

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

Biomedical Vacation Scholarship. 20 May 2011

Not available

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

Repair of topoisomerase-mediated and oxidative-stress induced DNA damage: novel factors and implications on neuronal function. 04 Feb 2010

DNA topoisomerases (Topos) regulate DNA topology ahead of important cellular processes such as transcription, replication, and repair. Topos generate transient DNA breaks in which the Topo is attached to DNA via a covalent phosphotyrosyl bond. Failure to re-ligate these intermediates leads to persistent DNA breaks, which ultimately needs to be repaired. One such repair mechanism involves the hydrolytic cleavage of the phosphodiester bond between the stalled Topo and DNA. The prototype enzyme for such an activity is TDP1, which is also involved in the repair of a variety of oxidative 3 -termini and mutation of which is associated with the neurological disorder SCAN1. Despite this important catalytic function fulfilled by TDP1, it remains the only human enzyme that displays this activity. Here, we aim to (1) characterise and identify novel mechanisms for the repair of DNA topoisomerase-mediated and/or oxidative stress-induced DNA breaks, using a combined approach of yeast genetics and bi ochemical analysis (employing synthetic oligonucleotide substrates). (2) Define the impact of defective repair of oxidative and Top1-mediated DNA breaks on neural cell fate. In particular, we aim to examine the impact on mitochondrial genome stability, using a combination of biochemical, microscopical, and whole animal approaches.

Amount: £252,290
Funder: The Wellcome Trust
Recipient: University of Sussex

A Multi-Site Study of Socially Engaged Art in Public Health Research within Low Income Settings. 02 May 2013

There is increasing pressure for those working in community-based biomedical research to engage more with outside communities. This is justified by statements around democratising science and supporting two-way dialogue. Still, the underlying beliefs and assumptions driving engagement in practice are rarely explored and are not always understood by those involved, and the impacts of these activities are not always captured. Socially engaged art (SEA) may provide a unique space in which genuine e ngagement can take place. The aim of this research is to identify the impact and potential of SEA as a tool for community engagement (CE), allowing for open dialogue and addressing power imbalances between researchers and communities. This aim will be addressed by using two/three in-depth studies of SEA practice within the context of biomedical community-based research across different social, cultural and political contexts. Ethnographic and participatory methods will be used to explore the behaviours and attitudes of researchers, artists and other participants in the process and how these interact. As well as exploring the creative process the research will investigate the reactions and interpretations of the outputs of these works on local audiences. Outputs will hold relevance to research governance, research programmes, funders, NGOs and engagement practitioners.

Amount: £94,364
Funder: The Wellcome Trust
Recipient: University of Sussex

Adoption of rapid ethical appraisal as a practical method of assessing ethical issues relating to biomedical research projects in Ethiopia. 04 Jun 2009

The proposed research will test whether Rapid Ethical Assessment can be introduced as a mainstream tool to enhance biomedical research ethics appraisal in Ethiopia. Review of literature will shape a quantitative study to assess the most important issues to have affected research ethics review todate. A qualitative study will then explore deeper sociological, anthropological and ethical dimensions to the issues surrounding ethical appraisal. From the information gathered, tools based on the Rapid Ethical Assessment used in the Gambia will be developed and presented at a one-day stakeholder workshop. After feedback from participants, the tools will be piloted in at least three community-based epidemiologic research projects in Ethiopia. Basedon evaluations made, the tools will be further refined, and presented to a wider audience through a second 3-5 day workshop. A database made up of Rapid Ethical Assessments preceding a range of studies will be compiled, and will beavailable to interested researchers, on application.

Amount: £96,939
Funder: The Wellcome Trust
Recipient: University of Sussex

The role of RGC-32 in Epstein-Barr virus mediated cell-cycle deregulation. 30 Apr 2009

These studies will probe the role played by the novel cell-cycle regulator RGC-32 in the EBV-driven transformation process. This research will study the regulation of RGC-32 expression during EBV transformation and in EBV-infected cell-lines, investigate the mechanism of action of RGC-32 and its role in normal cell-cycle regulation and dissect the structure and function of the protein. Key goals: 1) To study the regulation of RGC-32 expression in EBV-infecetd cells. 2) To study the role of RGC-32 in B-cell transformation by EBV. 3) To probe the mechanism and consequence of CDK1 activation by RGC-32 using: a. Human cell biology and biochemistry b. The Xenopus laevis oocyte system c. Knock-out genetics in the chicken DT40 cell system. 4) To probe the structure of RGC-32 using X-ray crystallography.

Amount: £259,609
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

Wellcome Trust Brighton and Sussex Centre for Global Health Research 05 Dec 2012

There have been unprecedented scientific advances in genetics and genomics which are likely to translate into major improvements for human health. However, these advances will only widen the existing equity gap between high-income countries and low- and middle- income countries (LMICs), which disproportionately bear the burden of poor health, if LMIC populations, their scientists and health practitioners are not fully engaged. Given the recent expansion in funding for genomic research in Africa that this gap has driven, there is an urgent need to support the development of LMIC researchers in genomic science within a framework that addresses the ethical, legal and social implications of such research for individuals and their communities. Our vision, therefore, is to contribute towards improving the health of some of the world's poorest people by equipping high calibre researchers to undertake excellent research that will impact on important, locally-relevant global health problems. Our Centre* will build capacity for independent research at three LMIC partner institutions, supporting environments that empower scientists to contribute to a wider African research enterprise. Playing to our collective strengths, the Centre will focus on supporting research training in Genomics and Global Health for two key groups: a) 'high-flying' individuals with the potential to develop into world-class, independent scientific leaders who will receive tailored support and mentorship to develop their scientific ideas and submit competitive funding proposals b) a broader group of academic staff and postgraduate students, in order to build academic research and teaching expertise through a series of workshops and scientific meetings and an online resource centre. The Centre will draw on the applicants' expertise in public health, epidemiology, genetics and genomics, public engagement, ethics and policy, in partnership with collaborating centres. We will take a novel interdisciplinary approach where medical humanities are represented alongside basic and clinical science and the importance of fostering cross-cutting research is recognised and exploited. This initiative builds on recent university investments and efforts in global health at Brighton and Sussex Medical School (BSMS) and the University of Sussex, meaning the UK base is embedded within a rich university environment that has a long track record of progressive engagement with LMICs. * The term 'Centre' refers collectively to all applicant institutions: BSMS/University of Sussex (UK), Nowgen (UK), the Armauer Hansen Research Institute (Ethiopia), the Research Foundation in Tropical Diseases and Environment/Faculty of Health Science, University of Buea (Cameroon) and the Institute of Endemic Diseases (Sudan).

Amount: £251,014
Funder: The Wellcome Trust
Recipient: University of Sussex

Epidemiological mapping of podoconiosis in Ethiopia . 06 Dec 2012

This Training Fellowship will enable documentation of the overall prevalence and distribution of podoconiosis in Ethiopia. Podoconiosis is a non-infectious Neglected Tropical Disease that affects an estimated 4 million people across tropical Africa, but no nationwide map is available in any endemic country. The Training Fellow will develop a nationwide mapping technique drawing on the expertise of the KEMRI-Wellcome Trust Malaria Public Health & Epidemiology group and the School of Public Health , Addis Ababa University. Following training in Spatial Epidemiology in Public Health at the London School of Hygiene & Tropical Medicine, the Training Fellow will plan and carry out a nationwide survey, through which a representative sample of individuals will be selected for clinical examination, rapid antigen testing and (in a subsample) antifilarial antibody testing to exclude filarial lymphoedema. Information on topographic and environmental factors will also be collected, and GIS modeling used to identify factors associated with disease and (in a validation subset) predict disease presence. Information on podoconiosis prevalence and distribution will enable podoconiosis control policy to be generated in Ethiopia. The mapping technique developed will make possible control-orientated mapping of podoconiosis in other endemic tropical countries.

Amount: £272,808
Funder: The Wellcome Trust
Recipient: University of Sussex

Neurodegeneration and aging: roles for DNA single-strand break repair. 23 Jun 2008

The SSBR proteins TDP1 and Aprataxin are mutated in two distinct neurological diseases; spinocerebellar ataxia with axonal neuropathy-1 (SCAN1) and ataxia oculomotor apraxia-1 (AOA1). The goal of this proposal is to (1) Characterise mechanisms of SSBR in primary neural cells using a combination of in vitro biochemical assays (employing synthetic oligonucleotide substrates) and cellular chromosomal DNA repair assays (employing the alkaline comet assays). I propose to define the intermediates that accumulate in neural cells that are defective in SSBR using biochemical approaches and to characterise novel factors in this pathway using yeast 2-hybrid and co-immunoprecipitation experiments. (2) Elucidate the impact of un-repaired SSBs on neural cell fate, with emphasis on transcriptional competence and survival of primary neural cells. (3) Evaluate the neuroprotective effect of SSBR in vivo, by measuring specific behavioural and physiological end points in wild type and SSBR-defective mouse model systems.

Amount: £653,466
Funder: The Wellcome Trust
Recipient: University of Sussex

The Imp2 mRNA binding protein: Roles in morphogenesis and differentiation of the mammalian inner ear. 20 Oct 2005

The inner ear develops from the otic placode, a specialised patch of neuroectoderm adjacent to the developing hindbrain. A major goal is to understand the molecular mechanisms that convert this patch of cells into the complex adult structure. IGF signalling is associated with inner ear development, but how inner ear IGF activity is controlled is not known. Previously we isolated the Igf2 mRNA binding protein, Imp2, and have shown it is expressed in different sensory epithelia during development, including the inner ear. In this project we will use gain and loss of function approaches in transgenic mice to determine the function of Imp2 in inner ear development. We will test the hypothesis that Imp2 is a key regulator of IGF activity, controlling morphogenesis and differentiation in the developing inner ear. Key Goals: Determine whether Imp2 regulates localised differential growth of cells in the otic epithelium Determine whether Imp2 affects hair cell differentiation Determine the effects of Imp2 on IGF1 & IGF2 expression Determine whether Imp2 regulates otic neuroblast proliferation and/or migration Determine the fate of Imp2 expressing cells in the mature inner ear Investigate the association of Imp2 with hair cell repair/regeneration

Amount: £231,619
Funder: The Wellcome Trust
Recipient: University of Sussex

Roles of the supporting cells in the mechanical responses and neural excitation in the mammalian cochlea. 27 May 2009

Pillar and Deiters cells have conspicuous arrangements of parallel microtubules and microfilaments spanning the cell bodies and bundled up by cross-linking proteins. These cells differ from the hair cells, in that they extend from the reticular lamina to the basilar membrane, the vibrations of which determine the excitation of the mechano-sensitive hair cells. The rigidity of the reticular lamina depends on the apical junctions between the pillar, Deiters cells and the hair cells, and the cytosk eletal arrangements at their apices. Besides, pillar and Deiters cell bases sit on the basilar membrane and they should, therefore, contribute to its stiffness and help direct the amplifying forces generated by the motile outer hair cells. In this project I aim to examine the roles of the apical junction complexes and the microtubule bundles of pillar and Deiters cells in cochlear mechanical responses and neural excitation. To accomplish these aims I propose to: 1) generate mouse lines in which structural proteins are specifically deleted in the pillar and Deiters cells, 2) determine the effects of those changes on cochlear structure and development and 3) determine the effects of these genetic manipulations on cochlear mechanical and neural responses in vivo.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University of Sussex

Student Elective Prize for Mr Christopher Ball 29 Aug 2008

A retrospective study into the management of Cervical Spine injuries over a 12 month period, with specific interest into the adherence to the Canadian CT Cervical Spine Rule over the NEXUS rule

Amount: £1,600
Funder: The Wellcome Trust
Recipient: University of Sussex

The tectorial membrane and the sensory hair bundles of the inner ear: mechanisms of development and effects of deafness-related mutations. 04 Feb 2009

The aim is to understand the development, maturation and dysfunction of two key components of the cochlea, the tectorial membrane and the sensory hair bundle. Analysis of mice with mutations affecting the structure and attachment of the tectorial membrane, and misexpression of tectorial-membrane proteins, will reveal the molecular mechanisms underlying the normal development of this matrix and how its constituent elements are organised. Mouse models will be used to analyse why mutations in the g ene encoding Tecta cause progressive forms of hereditary deafness and if mutated Tecta protein exacerbates the detrimental effects of loud sounds. Ectopic expression of the hair-bundle link protein stereocilin will be used to determine if it can mediate tectorial-membrane attachment. Targeted inactivation of the enzymatic and G-protein-mediated activities of two orphan receptors of the hair bundle (Ptprq and Vlgr1) will assess structural roles for these proteins, and imaging techniques will dete rmine if they can be force-activated. A mouse model for a novel human mutation causing aminoglycoside-induced hearing loss will be created to study how the mutant hair-bundle protein enhances sensitivity to aminoglycosides. These studies will determine how the tectorial membrane and the hair bundle develop, and reveal how environmental factors interact with mutations in inner-ear proteins.

Amount: £1,268,129
Funder: The Wellcome Trust
Recipient: University of Sussex