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Results

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

Gene-environment studies in podoconiosis. 11 May 2010

Podoconiosis (endemic, non-filarial elephantiasis) is a common but under-researched condition found predominantly in tropical Africa. A strong research program has been developed over six years through collaboration between academics from Addis Ababa University and Brighton & Sussex Medical School, and a podoconiosis Patient Association in southern Ethiopia. Through the research described below, we intend to expand the program to include geological and mineralogical research into the environment al trigger to complement further genetic studies. We plan first to use stored blood samples from patients and controls in southern Ethiopia to confirm the association between Class II HLA genes and susceptibility to podoconiosis. In parallel with this, we will collect salivary DNA samples from 400 cases and 400 controls in a recently described endemic site in North West Cameroon. We will genotype the top 80 single nucleotide polymorphisms (SNPs) identified by our earlier GWAS and perform HLA f ine mapping on all samples, and do HLA typing and sequencing in a subset. Finally, in an eight-site comparative study in four regions of Ethiopia, clinical, epidemiological, geological and topographical information will be gathered and linked using GIS methods, and soil and water samples taken for mineralogical and chemical analysis.

Amount: £550,000
Funder: The Wellcome Trust
Recipient: University of Sussex

Biomedical Vacation Scholarship 14 Jun 2010

Not available

Amount: £10,080
Funder: The Wellcome Trust
Recipient: University of Sussex

Analysis of genome maintenance pathways by live cell imaging. 25 Feb 2009

Maintaining a stable genome is a vital necessity for all cells. This is achieved by coordinating DNA replication, DNA repair and the accurate segregation of the replicated sister chromatids (or homologous chromosomes in the case of meiosis) among the daughter cells. All these processes are subjected to complex and dynamic regulation and take place in different cellular compartments at different times in the cell cycle. Accurate and extensive observation and analysis of these processes in living cells is crucial to unravel the complex mechanism of the different genome maintenance pathways and requires advances imaging technologies. This proposal comprises a variety of research projects that are primarily focused on the analysis of genome maintenance pathways using live cell imaging. We are proposing to analyze chromosome segregation during meiosis, visualize the formation and dissolution of DNA double strand break repair complexes, checkpoint proteins, centrosomes, chromosomal passenger proteins during mitosis, and vesicle trafficking in neurons. What these projects have in common is a requirement for the analysis of living cells using up to date imaging technology. A Delta Vision imaging station would therefore be of great benefit for our research on genome stability.

Amount: £191,078
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 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

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

A new class of genes containing small Open Reading Frames: cellular and molecular function of the encoded peptides. 06 Apr 2009

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: £1,600,995
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

Biomedical vacation scholarship. 29 May 2009

Not available

Amount: £12,600
Funder: The Wellcome Trust
Recipient: University of Sussex

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