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Results

Global Flows, Human Rights, Sexual And Reproductive Health: Ethnographies of Institutional Change in the Global South. 28 Mar 2011

The two-day the conference will bring together experts from across the social sciences to critically reflect on the way in which human rights ideas and conventions are shaping the development discourse and ethical issues relating to sexual, maternal and reproductive health in the countries of Asia, Africa and Latin America. The conference will also provide a space to debate broader issues in the gendered politics of rights such as whether rights are an appropriate means for achieving sexual and reproductive health of the poor andmarginalised and to what extent a rights focus on the bodies of poor women forms part of a wider set of exclusionary discourses.

Amount: £1,850
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

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

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

Impact of DNA non homologous end joining on stem cell function in vivo. 30 Apr 2008

DNA double strand breaks (DSBs) arise from oxidative damage and following radiation treatment. Their impact on development and particularly on stem cells is unclear but is topical and important. As a result of basic research, an exquisitely sensitive technique to monitor DSB repair in vivo has been recently developed. Additionally, we recently characterised a mouse mutated in DNA ligase IV (LigIVY288C), a component of DNA non-homologous end-joining (NHEJ), the major DSB repair pathway. We showed that haematopoietic stem cell (HSC) numbers and function are diminished in LigIVY288C mice demonstrating that unrepaired DSBs impact on stem cells. Here, we will pursue our analysis by monitoring radiation-induced DSB repair in three stem cell compartments, the HSCs, the ventricular and sub-ventricular zone of the developing embryonic brain, and the intestinal crypt. For this we will use normal mice. We will also exploit LigIVY288C mice to examine the impact of impaired NHEJ in the embryonic br ain and intestinal crypt, where stem cells can be readily identified. Our major focus will be on embryonic neuronal development since microcephaly is a feature of LIG4 syndrome, a disorder caused by mutations in LigIV, and since our preliminary studies have shown abnormalities in the LigIVY288C embryonic brain.

Amount: £246,628
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

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