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Results

VALUE IN PEOPLE AWARD. 30 Aug 2006

Not available

Amount: £200,000
Funder: The Wellcome Trust
Recipient: University of Sheffield

Analysis of the role played by CRP family transcriptional regulators in the pathogenesis of Mycobacterium tuberculosis. 09 Feb 2006

This proposal centres on defining the roles of regulatory genes of the CRP family and their relationship to cAMP in the pathogenesis of Mycobacterium tuberculosis, the causative agent of TB. It builds upon our recent work in which we showed that the Rv3676 gene coding for a cAMP-receptor protein (CRP)-like protein is required for a normal infection in a mouse model of TB and that Rv3676 is a direct transcriptional regulator of, among other genes, rpfA, coding for a resuscitation promoting factor, implicating Rv3676 in the reactivation of dormant infections. These observations are very significant because most cases of symptomatic TB occur by reactivation of dormant bacteria. Thus, we wish to determine: the signal perceived by Rv3676, and its relationship to Rv1264, a pH-responsive adenylyl cyclase; the architecture of Rv3676-regulated promoters; and whether Rv3676 has protein-binding partners, with particular focus on the exciting possibility that Rv3676 interacts with one of the WhiB class of actinomycete-specific transcription regulators. In addition, by adapting the approaches (mutant isolation, phenotypic analysis, transcript profiling and biochemical analysis) used by the applicants to reveal the role of Rv3676 in pathogenesis, we propose to characterize a second mycobacterial CRP family member encoded by gene Rv1675

Amount: £254,398
Funder: The Wellcome Trust
Recipient: University of Sheffield

Antenatal screening and the gendering of genetic responsibility. 12 Jun 2006

BACKGROUND Antenatal blood tests for genetic defects are offered to women throughout pregnancy. During this process male partners are tested only where a combined positive male and female test could result in foetal abnormality such as sickle cell anaemia. Little is known about the gendered nature of this process and the impact it has on lay feelings of genetic responsibility. For example, as the key targets of testing, do women feel more responsible than men for genetic defects? How does this impact on parental decision-making when defects are found? A better understanding of male and female conceptions of this process could enhance practice in antenatal screening and genetic counselling. METHOD This research is a pilot study thus sample numbers will be small. The research will be conducted in the city of Sheffield. In order to fully explore the gendered nature of prenatal screening, views will be sought from both pregnant women and their partners. Twenty pregnant women and their male partners will be interviewed individually using semi-structured interviews. The same interview questions will be used for both partners. These questions will focus on screening procedures and the decision- making process: for example, which tests are opted for and why? Do couples decide which tests to opt for together? A diverse sample will be accessed through community and hospital midwives from two distinct locations in Sheffield. In order to adequately explore the screening process, women in the study will be at least 17 weeks pregnant. On collection of data, interviews will be transcribed and themes developed.

Amount: £16,175
Funder: The Wellcome Trust
Recipient: University of Sheffield

Mechanisms and consequences of neutrophil survival in hypoxia 06 Dec 2005

Neutrophils are important for innate immunity and are adapted to function at sites of inflammation which are relatively oxygen deplete. I have shown that physiological hypoxia (3 kPa O2) inhibits neutrophil apoptosis in vitro, a process directly regulated by the oxygen-sensitive transcription factor hypoxia inducible factor-1a (HIF-1a). HIF-1a is itself post-translationally regulated by a group of oxygen-sensitive enzymes, the prolyl hydroxylase domain containing enzymes (PHDs). 3 PHD isoforms are described and are expressed in neutrophils. In the presence of oxygen these enzymes hydroxylatethe HIF a subunit causing its rapid proteolytic destruction. I aim to elucidate the mechanisms regulating HIF-1a expression in neutrophils and determine the importance of these pathways for neutrophilic inflammation in vivo. My specific aims are to: i). Characterise PHD expression in neutrophils and effects on neutrophil function and apoptosis, comparing neutrophils from PHD1-3 deficient mice and mice with alteration of other HIF pathway componentsii). Examine consequences of PHD deficiency/HIF stabilisation in in vivo

Amount: £741,138
Funder: The Wellcome Trust
Recipient: University of Sheffield

University of Sheffield Centre for BioImaging 31 Oct 2005

We aim to establish a high-resolution light microscopy facility to enable researchers in the Departments of Biomedical Science (BMS) and Molecular Biology and Biotechnology (MBB) (both rated as 5* in the last RAE) at the University of Sheffield, to carry out direct visualisation of biological molecules, and their interactions, in their natural cellular, tissue or organismal environment. The principal applicants already have funding in place to pursue fundamental biological questions that require such sophisticated imaging but it is envisaged that this will be a multiuser facility available to many other scientists in BMS and MBB, which will be run on an equitable basis. Bringing the apparatus under one roof with a dedicated postdoctoral worker in place to manage the facility will greatly enhance productivity, facilitate the development and implementation of state-of-the-art technologies in light microscopy and provide access to such technologies to less experienced users. The bid includes requests for multi-photon, confocal and DeltaVision microscopes and the facility will also include a TIRF microscope (already purchased by BMS). This combination of microscopes will provide the necessary flexibility so that each user can visualise samples under optimum conditions. Given the rapid technological developments in this area, this facility will also promote the dissemination of information and ideas.

Amount: £604,241
Funder: The Wellcome Trust
Recipient: University of Sheffield

Value in People Award. 18 Jul 2007

Not available

Amount: £200,000
Funder: The Wellcome Trust
Recipient: University of Sheffield

Is subcortical input to the basal ganglia via the thalamus organised into parallel, functionally segregated channels ? 12 Oct 2006

Analysis of parallel, partially closed-loop projections connecting the cerebral cortex with the basal ganglia has been a dominant feature in basal ganglia research for the past 20 years. Although of comparable anatomical significance, input from the thalamus has received much less attention. The likely importance of this input was, however, emphasised in our recent proposal that a series of phylogenetically older, looped connections exist between the basal ganglia and important structures in the brainstem, including the midbrain superior colliculus (SC). A general feature of subcortical input to the basal ganglia (striatum) is that it arrives via relays in the thalamus (Appendix Fig 1). Thus, a direct test of the 'subcortical loops' hypothesis will determine whether the multiple thalamic relays that receive input from the SC and provide output to the striatum can be viewed as anatomically and functionally segregated channels. We propose a series of convergent anatomical, physiological and behavioural investigations to test this hypothesis. Given the evolutionary conserved nature of subcortical brain architecture, understanding this circuitry will help us appreciate how this currently poorly understood component of the basal ganglia might contribute to the basal ganglia-related dysfunctions that afflict humans.

Amount: £334,830
Funder: The Wellcome Trust
Recipient: University of Sheffield

The mechanism of Histone Deacetylase 1 function in specification of neural fates in the developing zebrafish CNS. 06 Feb 2007

Hdac1 is essential for transformation of neural progenitors in the developing zebrafish CNS into differentiated neurons and oligodendrocytes. The overall aim is to elucidate how Hdac1 exerts direct transcriptional control over this process. It remains unclear if Hdac1 functions in proliferating neural progenitors, in the post-mitotic descendants of neural progenitors, or if Hdac1 is required in both of these CNS compartments. Moreover, the spectrum of target genes that are subject to Hdac1-depen dent transcriptional control in the CNS is unknown, as are key features of the epigenetic control mechanisms modulated by Hdac1 function. Accordingly, the project has the following key goals: 1. To rescue the neural defects in the hdac1 mutant CNS using stably integrated transgenes which target Hdac1 function to proliferating neural progenitors, their post-mitotic progeny, or both CNS compartments. 2. To identify sets of genes (a) that are directly repressed by Hdac1 and (b) whose expr ession is Hdac1-dependent, in the developing CNS 3. To identify direct interactions between Hdac1 and cis-regulatory elements of target genes. 4. To elucidate the Hdac1-dependent changes in the patterns of chromatin modifications associated with promoters of genes that are regulated by Hdac1 function in the developing CNS.

Amount: £226,731
Funder: The Wellcome Trust
Recipient: University of Sheffield

Analysis of parkin/pink1 functional pathway in a Drosophila model of Parkinsondisease. 27 Feb 2007

Parkinson s disease (PD) is a common neurodegenerative disorder caused by the progressive loss of dopaminergic neurons, however, the pathologic causes remain unclear. Recently, mitochondrial dysfunction has again received much attention with the findings that the PD-linked genes parkin and pink1 may act in a common pathway to maintain mitochondrial integrity. Drosophila models for mutations in parkin and pink1 recapitulate many features of PD and have become leading model systems with which to s tudy the molecular and genetic mechanisms of PD. Here we propose to use the Drosophila parkin and pink1 models to elucidate the functional pathway in which they act. We shall employ proteomic techniques to identify novel targets of pink1 activity in vivo by isolating endogenous binding partners. We shall also test whether pink1 regulates the activity of parkin by molecular interaction or by an indirect mechanism. In addition, we shall also determine whether parkin and/or pink1 play a role in mit ochondrial fission or fusion events by testing for molecular and genetic interactions with known fission/fusion factors. We also propose to use unbiased genetic screens to uncover other factors in the parkin/pink1 functional pathway.

Amount: £322,238
Funder: The Wellcome Trust
Recipient: University of Sheffield

In vivo regulation of neutrophil function by hypoxic signalling. 03 Jul 2007

The unique combination of optical transparency and genetic manipulability make Zebrafish larvae an ideal model for the in vivo study of neutrophil behaviour. Hypoxic signalling is important in determining the outcome of neutrophilic inflammation, but much is unknown about how hypoxic signalling influences inflammation at a molecular level. Using well established transgenic Zebrafish models of inflammation, we will study multiple aspects of neutrophil behaviour during experimentally-induced infla mmation in vivo, and observe the effects of physical, pharmacological and genetic activators of the hypoxic signalling pathway on neutrophil behaviour. Having validated the system for the study of hypoxic signalling, we will study the effect of various gene manipulations on neutrophil behaviour in vivo, and on gene expression profiles. Firstly, we will use mutants in vhl1, the Zebrafish homologue of human vhl, and study in vivo inflammation in heterozygotes and homozygotes. We will compare these mutants to FIH mutants, and to combination mutant/morphants to determine key control points. Finally, we will address the question of the degree of HIF dependence of different neutrophil responses to hypoxic signalling, by using a myeloid specific DN-expressing transgenic line to block the HIF component of hypoxic signalling in the various models described above.

Amount: £188,853
Funder: The Wellcome Trust
Recipient: University of Sheffield

Genome wide analysis of a novel human mRNA export pathway. 10 Jul 2007

We have identified a novel mRNA export factor, UIF likely to define a new mRNA export pathway in human cells. UIF associates with mRNA export factors UAP56 and TAP and can promote export of an otherwise inefficiently transported mRNA. Mass spectrometry reveals that UIF copurifies with the SSRP1 component of the FACT chromatin remodeling complex. Here we will carry out a genome wide analysis of the dependency of mRNAs on UIF, ALY, DDX39+UAP56 and the FACT complex for export. We will define the mR NA substrates for the new UIF pathway using immunoprecipitation of UIF, extraction of bound mRNA followed by microarray analysis (RIP-CHIP). Secondly we will knockdown UIF, ALY/REF, UAP56 together with the paralogue DDX39 and the SSRP1 and SPT16 components of FACT. Total and cytoplsmic RNA will be analysed using microarrays to determine which pathways individual mRNAs use during export. We will characterize the RNA binding properties of UIF using cross-linking immunoprecipitation (CLIP) to dete rmine where it binds on mRNAs and use deletions and mutations to define the RNA binding domain. We will also examine whether UIF has the ability to switch TAP from a low to high affinity RNA binding state.

Amount: £305,231
Funder: The Wellcome Trust
Recipient: University of Sheffield

Physiological importance of SK2 in whole body K+ homeostasis. 03 Jul 2007

Regulated K+ secretion by the renal collecting duct is critical for regulation of whole body K+ homeostasis. Although the K+ channel ROMK plays an important role in this process, it is clear that additional K+ channels are also involved, e.g. BK channels in response to changes in tubular flow and dietary K+. Previous and preliminary work suggests that SK2 also plays a role in this process. In preliminary experiments plasma K+ in SK2 KO mice was increased and the fractional excretion of K+ was reduced, consistent with a role for SK2 in K+ secretion. The aim of the proposed project is to examine this further, using in vivo, molecular, fluorescence and electrophysiological approaches. Experiments will compare wildtype and SK2 KO mice examining whole renal function under control, volume expanded conditions and in response to changes in dietary K+. Molecular and fluorescence approaches will determine the cellular location of SK2. These experiments will also examine whether different K+ diets alter SK2 expression. Finally, electrophysiological studies will be used to identify SK2 at a functional level and examine physiological regulation. Elucidating the mechanisms underlying renal K+ secretion will increase our understanding of renal physiology in both health and disease.

Amount: £247,845
Funder: The Wellcome Trust
Recipient: University of Sheffield

Is there a future for patent ethics committees? 27 Oct 2006

The aim of the project is to provide a preliminary exploration of the issues which may arise with the creation of ethics committees attached to national patent offices or the European Patent Office to advise on individual patent applications involving morally sensitive biotechnological inventions. Although the creation of such 'patent ethics committees' (PECs) has been recommended by the European Group on Ethics and the European Parliament and, furthermore, Norway has taken the lead in appointing the first PEC, there is as yet no other international precedent and no systematic analysis of the ambit of operation of such committees or the nature of their possible relationship to existing national and supranational research ethics committees (RECs). The aim of the pilot project would be to identify the potential synergies and tensions, conflicts, duplication or disjunctions that the creation of such committees may generate between the ethical regulatory controls· on research and the additional ethical controls on patents, with a view to providing a map to chart future collaborative research with other leading partners internationally. In terms of methodology, this pilot project will build on the results of an EU funded project on the law and ethics of human embryonic stem cell research (I" January2005 - June 2006), whose preliminary findings have highlighted a possible tension between the proposal to create an ethics review committee attached to the European Patent Office and the existing system of ethical review of biomedical research in Europe. The research fellow will undertake a review of the role of existing national research ethics committees in the UK, Norway, Japan and the US on the oversight of research involving the application of new biotechnologies in biomedical research with human subjects to provide a map of the gaps, loopholes and areas of ethical or legal controversy or uncertainty at institutional and normative level. This will be followed by a comparative analysis to chart a map of the emerging ethical and legal issues regarding the creation of PECs for future consideration.

Amount: £29,018
Funder: The Wellcome Trust
Recipient: University of Sheffield

Understanding the role of contact networks in the epidemiological and evolutionary dynamics of zoonotic disease. 30 May 2007

I will investigate the link between contact networks, epidemic processes and pathogen evolution by building a detailed dataset on host population structure, disease incidence and virus samples from a region of endemic canine rabies in Tanzania. I propose to develop a hierarchical suite of spatial models to determine how population structure influences transmission and spatiotemporal disease dynamics. I will explore the implications of heterogeneous and partial control on epidemiological dynamics and on long-term (evolutionary) life-history characteristics of the rabies virus. Epidemiological theory has facilitated development of models that have proven immensely valuable to understanding disease dynamics. However, detailed application to specific cases is hampered by lack of precise knowledge of the transmission process. Increasingly available high-resolution pathogen genetic data promises to revolutionize our understanding of transmission dynamics, though essential analytical meth ods must be developed for reconciling epidemiological and genetic data. I will develop methods for combining observational records with knowledge of spatiotemporal disease dynamics to refine construction of phylogenetic and epidemiological trees. More broadly the goal of this fellowship is to use rabies as a model system for understanding the role of realistic network structure on the epidemiology and evolution of generalist pathogens.

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

Hedgehog signalling in zebrafish: Functional analysis of the pathway components. 10 Jul 2007

Exactly how Hh signalling is transduced and how it controls both cell fate specification and cell proliferation is still not well understood. Although the core components of the signal transduction pathway have been highly conserved during evolution, significant differences in the intracellular components exist between species. We aim to clarify the nature of this divergence in mechanisms and to elucidate the molecular interactions and processes that underlie the different outputs of Hh signalling. Specifically we will: 1) investigate the functional differences between the Hh receptors encoded by patched1 and patched2 and identify genes that link the Hh signal to growth in the zebrafish. 2) Use proteomic approaches to identify new components of the signalling pathway and characterise the interactions between known components. 3) Identify and characterise mutant alleles of genes encoding intracellular components of the pathway in the zebrafish and use double mutant analysis to elucidate their functional interactions. 4) perform chemical genetic screens to identify small molecule agonists and antagonists that act at different points in the pathway.

Amount: £1,242,139
Funder: The Wellcome Trust
Recipient: University of Sheffield

Open Access Award. 31 Oct 2006

Not available

Amount: £20,000
Funder: The Wellcome Trust
Recipient: University of Sheffield

Value in People Award. 17 Oct 2007

Not available

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

Vacation Scholarships 2008. 27 May 2008

Not available

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

Student Elective Prize for Mr Ugochukwu Ihekwaba 29 Aug 2008

The correlations of Outcome from Herpes Simplex Virus Infections of the Central Nervous System with Virus Load as Determined by Quantitative Polymerase Chain Reaction (PCR)

Amount: £1,000
Funder: The Wellcome Trust
Recipient: University of Sheffield

Dissection of Frizzled function in cell polarity establishment in Drosophila. 09 Apr 2008

We are interested in how cells coordinate their polarity with their neighbours and the axes of the organism during animal development. The particular focus of this application is to continue our studies of the so-called core planar polarity genes. These encode a diverse group of proteins (including the receptor Frizzled) required for cell-cell communication, which during cell polarisation become asymmetrically distributed to the apicolateral junctions of cells. We aim to: 1) Understand h ow the core planar polarity proteins interact with each other and with the cellular trafficking machinery to achieve asymmetric distribution and coordination of polarity between neighbouring cells. 2) Investigate how the core planar polarity proteins control tissue morphogenesis in a range of contexts. 3) Identify new factors involved in coordination of cell polarisation and morphogenesis. To achieve these goals we will: 1) Develop new methodologies to study the dynamics of protein l ocalisation in vivo. 2) Apply existing knowledge of intracellular trafficking pathways and signals to the study of the core planar polarity proteins. 3) Genetically dissect planar polarity gene function and tissue morphogenesis in new contexts during Drosophila development. 4) Carry out in vivo RNAi screens.

Amount: £1,626,341
Funder: The Wellcome Trust
Recipient: University of Sheffield