New Scientist Study

PhD Project : Bioavailability and neurotoxicity of aluminium to the freshwater crayfish (Faculty of Life Sciences - The University of Manchester)

Wed, 18 Aug 2010 13:17:39 +0100

Bioavailability and neurotoxicity of aluminium to the freshwater crayfish Principal investigator(s): Professor Catherine McCrohan , Dr Keith White Funding: Project available for individuals with self arranged funding. Subject Areas Adaptive Organismal Biology Animal Biology Environmental Biology Integrative Neurobiology & Behaviour Physiology Toxicology Description Background and aims
Aluminium is ubiquitous in the environment, is bioavailable at neutral pH (Desouky et al., 2002) and is highly neurotoxic to freshwater invertebrates (Campbell et al., 2000). Aqueous Al is toxic to the crayfish via damage to the gills resulting in behavioural toxicity within 10 days of exposure (Alexopoulos et al., 2003). Recent unpublished work has shown that Al in the food is also bioavailable and is accumulated in certain tissues. The hypotheses are that Al is toxic to the crayfish, specifically the nervous system, and that this is due to accumulation in the tissues. The aims are to:
1. Examine partitioning of Al in the tissues (including haemolymph) with time.
2. Monitor potential sublethal toxicity of Al to the crayfish by examination of changes in behaviour (using standard behaviour measures plus additional methods to be developed during the course of the study)
3. Examination of electrophysiological properties of central neurones following in vivo exposure to Al, and in vitro.
Methods
. Metal analysis of tissues and water using inductively-coupled plasma optical emission spectroscopy (ICPOES).
. Behavioural monitoring
. Intracellular electrophysiological techniques to examine membrane conductances underlying electrical activity patterns (action potentials)
Related Publications Desouky, M, Jugdaohsingh, R, McCrohan, C R, White, K N & Powell, J J (2002) Aluminium-dependent regulation of intracellular silicon in the aquatic invertebrate Lymnaea stagnalis. Proc. Nat Acad. Sci. US, 99, 3394-3399. Campbell, M M, Jugdaohsingh, R, White, K N, Powell, J J & McCrohan, C R (2000) Aluminium toxicity in a molluscan neuron: effects of counterions. J. Toxicol. Environ. Health, Part A 59, 253-270. Alexopoulos, E, McCrohan, C.R., Powell, J.J. Jugdaohsingh, R. & White, K.N. (2003) Bioavailability and toxicity of freshly neutralised aluminium to the freshwater crayfish Pacifastacus leniusculus. Arch. Environ. Contam. Toxicol., 45, 509-514. Fee Band This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants.

PhD Project : The role of antibodies in vaccine-driven immune responses to parasites (Faculty of Life Sciences - The University of Manchester)

Wed, 18 Aug 2010 13:17:22 +0100

The role of antibodies in vaccine-driven immune responses to parasites Principal investigator(s): Professor Kath Else Funding: Project available for individuals with self arranged funding. Subject Areas Animal Biology Immunology Description Intestinal nematode parasites are incredibly prevalent infections of man. No effective vaccines exist to prevent infection of humans with these sorts of parasites. Mice can be protected against infection with murine nematode parasites by vaccination. The project investigates the mechanisms underlying the protection mediated by vaccination of mice normally susceptibility to the intestinal nematode parasite Trichuris muris. Using transgenic approaches it specifically explores the role of antibodies in vaccine induced immunity. A variety of contemporary immunological methodologies will be used including cell and tissue culture, immunohistochemistry, flow cytometry, gene expression analyses and immunoassay. Related Publications Dixon H., Little MC., and Else KJ. (2010) The protective Th2 response following subcutaneous vaccination against T. muris. International Journal for Parasitology 2010 May;40(6):683-93.
d'Elia R., Behnke JM, Bradley JE., and Else KJ. (2009) Regulatory T cells: a role in intestinal helminth survival and the control of host pathology. Journal of Immunology 182, 2340-2348
deSchoolmeester ML., Martinez Pomares L., Gordon S and Else KJ. (2009) The mannose receptor is not important in the expulsion of Trichuris muris. Immunology 126(2), 246-55.
deSchoolmeester ML., Manku H. and Else KJ (2006) The innate immune response of colonicepithelial cells to a nematode parasite does not differ between mouse strains that ultimately develop differentially polarised adaptive immune responses. Infection and Immunity, 74, 6280-6286
Little MC, Bell LV, Cliffe LJ and Else KJ. (2005) The characterization of intraepithelial lymphocytes, lamina propria leukocytes and isolated lymphoid follicles in the large intestine of mice infected with the intestinal nematode parasite Trichuris muris. Journal of Immunology 175, 6713-6722.
Fee Band This project has a Band 3 fee. Details of different fee bands are available for UK/EU or International applicants.

PhD Project : How do anti-mitotic drugs kill cancer cells? (Faculty of Life Sciences - The University of Manchester)

Wed, 18 Aug 2010 13:17:06 +0100

How do anti-mitotic drugs kill cancer cells? Principal investigator(s): Professor Stephen Taylor Funding: Project available for individuals with self arranged funding. Subject Areas Cell Biology Molecular Cancer Studies Description In 2007, over 12-million people were diagnosed with cancer. According to the American Cancer Society, at least one third of these individuals are not expected to survive the disease, making cancer the second most prevalent cause of death worldwide. Systemic chemotherapy forms the mainstay of cancer treatment, and agents that disrupt mitotic spindle assembly - so called 'anti-mitotics' - are commonly used to treat a wide variety of cancers. Traditional anti-mitotic agents include the microtubule toxins such as taxol, other taxanes and the vinca alkaloids, all of which have proven successful in the clinic. However, patient response remains highly unpredictable, and drug resistance is common. In addition, toxicity is a problem. To address these limitations, a new generation of anti-mitotic drugs is being developed. As the first wave of these new agents enters clinical trails, much hope rests on their outcome. Meanwhile, significant attention is being focused on trying to predict which tumour types are likely to respond. This project will focus on advancing our understanding of how cancer cells respond to anti-mitotic drugs. Related Publications 1. Keen, N. and Taylor, S. (2004). Aurora-kinase inhibitors as anticancer agents. Nat Rev Cancer 4, 927-36. 2. Girdler, F., K. Gascoigne, P.A. Eyers, K. Foote, C. Crafter, N. Keen, and Taylor, S. S. (2006) Validating Aurora B as an anti-cancer agent. J Cell Sci 119, 3664-75. 3. Girdler, F., Sessa, S., Patercoli, S., Villa, F., Musacchio, A., and Taylor, S. S. (2008) Molecular basis of drug-resistance in Aurora kinases. Chemistry & Biology 15, 552-562. 4. Gascoigne, K. and Taylor, S.S. (2008) Cancer cells display profound intra- and interline variation following prolonged exposure to anti-mitotic drugs. Cancer Cell 14, 111-122 5. Gascoigne, K.E. and Taylor, S.S. (2009) How do anti-mitotic drugs kill cancer cells? J Cell Sci 122, 2579-2585 Fee Band This project has a Band 3 fee. Details of different fee bands are available for UK/EU or International applicants.

PhD Project : Immune control of parasitic infection: Defining the role of the gel-forming mucins in protection against gastrointestinal nematodes (Faculty of Life Sciences - The University of Manchester)

Wed, 18 Aug 2010 13:16:48 +0100

Immune control of parasitic infection: Defining the role of the gel-forming mucins in protection against gastrointestinal nematodes Principal investigator(s): Professor Richard Grencis , Dr Dave Thornton Funding: Project available for individuals with self arranged funding. Subject Areas Biochemistry Cell Matrix Research Immunology Description Infection by gastrointestinal parasites (GI) is one of the most common types of parasitic infection in man and animals worldwide. Despite a considerable increase in our understanding of the immunoregulatory mechanisms that govern the adaptive and innate immune responses to GI parasites, progress in defining the mechanisms of protection has been slow. It is becoming clear that to remove such large multicellular pathogens from the GI tract largely revolves around the capacity of host molecules and cells to directly affect the normal metabolic activity of the parasites reducing their fitness, or indirectly alter the niche in which the parasites live making it unfavourable for parasite survival. The net result is that parasites become damaged, are not often killed by the host response but are unable to reproduce optimally and are ultimately expelled out of the host during normal intestinal transit.
Type 2 cytokine responses control a variety of cellular changes in the intestinal epithelia associated with host protection against GI nematodes. One important feature is goblet cell hyperplasia. Despite the fact that the major secreted factors from goblet cells are the gel-forming mucins a clear role for these molecules in mucosal protection against GI nematodes has only recently been identified in our laboratories. We have identified a critical role for mucins in protective immunity to the GI nematode, Trichuris muris. We hypothesise that gel-forming mucins are a major effector mechanism involved in protection against intestinal nematodes. The goals of this project are to define how gel-forming mediate protection against Trichuris muris and investigate its protective function against other intestinal nematodes.
This project will provide the student with a comprehensive training in a broad range of biochemical, immunological, proteomic, in vitro and in vivo approaches; these will include gel chromatographic, electrophoretic and centrifugal separations, tandem mass spectrometry, cell culture, immunoassay and mouse models.
Related Publications Hasnain,, S.Z., Wang, H., Ghia, J.E., Haq, N., Deng, Y., Grencis, R.K., Velcich, A., Thornton, D.J. and Khan, W.I. Mucin Gene Deficiency in Mice Impairs Host Resistance to Enteric Parasitic Infection. Gastroenterology (2010) 138 (5):1763-71
Thornton, D.J., Rousseau, K. & McGuckin, M. (2008) Structure and function of the polymeric mucins in airways mucus. Annual Review of Physiology 70, 5.1-5.28
Fee Band This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants.

PhD Project : Integrating genomic and proteomic research data with the primary literature - adventures in semantic publishing. (Faculty of Life Sciences - The University of Manchester)

Wed, 18 Aug 2010 13:16:28 +0100

Integrating genomic and proteomic research data with the primary literature - adventures in semantic publishing. Principal investigator(s): Professor Teresa Attwood Funding: Project available for individuals with self arranged funding. Subject Areas Bioinformatics Biomolecular Sciences Structural Biology Description New millennium biology is in crisis, overwhelmed both by data and publications describing those data: with 1.5 billion bases pouring monthly into DNA databases, and a new article appearing in Medline every 30 seconds, it is impossible to keep abreast of developments. As we systematically bury our knowledge in data and literature silos, we no longer know what we know, nor know how to find it!
To address these issues, new approaches are needed to manage, merge, interrogate and exploit 'big data' from modern, high-throughput genomic and proteomic experiments. Next-generation software (including new 'social' software) is required to turn the rapidly accumulating information into biochemical, biophysical and biomedical knowledge; new approaches are also needed to interface with the research hubs that build the databases on which modern biology now depends.
This project is an opportunity to work at this interface, building on collaborations with the curators of important protein databases (InterPro, UniProt, Gene3D, etc.) and with publishers. The broad aim is to integrate data in articles with information stored in databases, to be able to visualise and seamlessly interact with them in real time. The initial focus is on proteins, their families, their structures and interactions; in time, this will broaden to genes and genomic data.
We have built Utopia [1,2], software that semantically integrates visualisation and data-analysis tools with document-reading/management utilities. Utopia uses Web-services to marshal functionality from the Internet [3,4], gathering new tools within a single, user-friendly interface. Extending this work to focus explicitly on protein families [5] and protein-protein interactions, and taking advantage both of the results of the FEBS Letters experiment with the MINT protein interaction database and our semantic Biochemical Journal Experiment with Portland Press [2], this project will begin by exploring exciting new ways for visualising, analysing and understanding proteins and their interactions.
Related Publications 1. Pettifer S, Thorne D, McDermott P, Marsh J, Villeger A, Kell DB & Attwood TK (2009) Vis-ualising biological data: a semantic approach to tool and database integration. BMC Bioinformatics, 10, S18. 2. Attwood TK, McDermott P, Marsh J, Pettifer S & Thorne D (2009) Calling International Rescue: knowledge lost in data and literature landslide! Biochemical Journal, 424(3), 317-333. 3. Stockinger H, Attwood TK, Chohan SN, Cote R, Cudre-Mauroux P, Falquet L, Fernandes P et al. (2008) Experience using Web services for biological sequence analysis. Briefings in Bioinformatics, 9(6), 493-505. 4. Pettifer S, Thorne D, McDermott P, Attwood T, Baran J, Bryne JC, Hupponen T, Mowbray D & Vriend G (2009) An active registry for bioinformatics Web services. Bioinformatics, 25, 2090-2091 5. Hunter S, Apweiler R, Attwood TK, Bairoch A, Bateman A, Binns D, Bork P et al. (2009) InterPro: the integrative protein signature database. Nucleic Acids Res., 37, D211-5. Fee Band This project has a Band 1 fee. Details of different fee bands are available for UK/EU or International applicants.

PhD Project : Influence of silver nanoparticles on the invertebrate immune system (Faculty of Life Sciences - The University of Manchester)

Wed, 18 Aug 2010 13:16:12 +0100

Influence of silver nanoparticles on the invertebrate immune system Principal investigator(s): Dr Keith White Funding: Project available for individuals with self arranged funding. Subject Areas Adaptive Organismal Biology Animal Biology Environmental Biology Immunology Physiology Description Work at Manchester and elsewhere has shown that metal colloids such as aluminium is bio-available and toxic to invertebrates at neutral pH. Aqueous Al acts endogenously following accumulation from the food (e.g. Desouky et al., 2002) and exogenously following binding to the gills (e.g. Alexopoulos et al., 2003). Nanoparticles have experienced a huge expansion in recent years and the most common nano-material used in consumer products are nono-metals such as silver which also in a colloidal form.
Invertebrates have the ability to overcome infection through a non-specific but highly efficient immune system involving recognition and elimination of non-self material by circulating haemocytes Trace metals such as copper and zinc adversely affect immunocompetence in invertebrates and we have shown that Al colloids also impairs the ability of crayfish haemocytes to remove bacteria from the circulation in vivo (Ward et al., 2006).
The project will examine the effects of silver nanoparticles (silverNP) on the immune system of selected invertebrates, specifically to test the following hypotheses:
. Invertebrates exposed to silverNPs have an impaired immune response due to a reduction in the ability of circulating haemocytes to recognise, phagocytose and kill potentially infective agents.
. The response to exogenous silverNPs on the immune system of invertebrates possessing gills is a non-specific stress response resulting from respiratory dysfunction.
. The response to endogenous silverNPs is a metal-specific effect resulting from the toxic effects of the accumulated metal on haemocyte function.
The student will receive training in animal husbandry, metal analytical techniques, haemocyte culture, in vitro and in vivo measures of phagocytosis, recognition and killing of bacteria, electron microscopy.
Related Publications Alexopoulos, E, McCrohan, C.R., Powell, J.J. Jugdaohsingh, R. & White, K.N. (2003) Bioavailability and toxicity of freshly neutralised aluminium to the freshwater crayfish Pacifastacus leniusculus. Arch. Environ. Contam. Toxicol. 45, 509-514. Desouky, M, Jugdaohsingh, R, McCrohan, C R, White, K N & Powell, J J (2002) Aluminium-dependent regulation of intracellular silicon in the aquatic invertebrate Lymnaea stagnalis. Proc. Nat Acad. Sci. US, 99, 3394-3399. Ward, R.J, McCrohan, C R, & White, K N (2006) Influence of aqueous aluminium on the immune system of the freshwater crayfish Pacifasticus leniusculus. Aquatic Toxicol. 77, 222-228 Fee Band This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants.

PhD Project : Neural Networks in the Cerebral Cortex (Faculty of Life Sciences - The University of Manchester)

Wed, 18 Aug 2010 13:15:53 +0100

Neural Networks in the Cerebral Cortex Principal investigator(s): Dr Rasmus Petersen Funding: Project available for individuals with self arranged funding. Subject Areas Integrative Neurobiology & Behaviour Neuroscience Systems Neuroscience Description Each human brain contains more neurons than there are people on the planet. Everything that we experience or do involves large groups of neurons operating in concert. However, although we now know a tremendous amount about the biology of single neurons, we still know surprisingly little about how groups of neurons work together. The Petersen lab has state-of-the-art equipment that enables the activity of many neurons to be recorded at the same time, using silicon-bases polytrodes. The lab also has a strong track record in using advanced computational methods for analysing and modelling such data. The aim of this project is to use this technology to record simultaneously from as many neurons as possible from the somatosensory cortex. The rat whisker-barrel system is an ideal preparation for addressing this general question, since neurons with a common function (processing sensory input from a given whisker) cluster together in discrete, histochemically identifiable modules. This approach will lead to important insights into the critical question of how the collective activity of neurons achieves useful information processing. The project is inter-disciplinary and the successful student will be working as part of a cross-disciplinary team, incorporating skills in both biological experimentation and computer/mathematical modelling. There is the opportunity for the student, depending on their interests, to train in experimental methods, theoretical methods or both. The project could therefore suit applicants from either a biomedical or physical sciences background.
Related Publications . Petersen R.S., Panzeri S., Diamond M.E. (2001) Population coding of stimulus location in rat somatosensory cortex. Neuron 32:503-514.
. Petersen R.S., Brambilla M., Bale M.R., Alenda A., Panzeri S., Montemurro M.A., Maravall M. (2008) Diverse and temporally precise kinetic feature selectivity in the VPm thalamic nucleus. Neuron 60: 890-903.
Fee Band This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants.

PhD Project : Water quality and ecology of an urbanised river recovering from pollution (Faculty of Life Sciences - The University of Manchester)

Wed, 18 Aug 2010 13:14:47 +0100

Water quality and ecology of an urbanised river recovering from pollution Principal investigator(s): Dr Keith White Funding: Project available for individuals with self arranged funding. Subject Areas Adaptive Organismal Biology Environmental Biology Toxicology Description The River Irwell is a higher urbanised system as much of the lower reaches are within the cities of Manchester and Salford. In common with many urban rivers the channel is subject to modification to reduce flooding. The lower reaches of the Irwell have however been further modified as it forms the upper part of the Manchester Ship Canal (MSC). The MSC was designed to accommodate large vessels and therefore the depth and width of this section of the river results in a large reduction in current velocity and, hence, potentially a marked change in hydrology and ecology. The ecology of the river will also be affected by industrial and sewage pollution although recent capital investment by the water industry is predicted to have improved water quality.
The overall aim of the studentship is to examine the water quality and ecology at the interface between the lower River Irwell and the upper reaches of the MSC. This will include an examination of the relationship between past and present water quality and the changes in the ecology of the Irwell with particular reference to the planktonic (phyto- and zooplankton) and benthic invertebrate communities. The study will include an examination of the degree of contamination of the water, sediments and biota arising from past and present trace metal pollution. The study will include the development of a computer-based model to assist in the future management of water quality and ecology of the system. The project will therefore involve field and laboratory sampling and analysis of water quality, plankton and benthic invertebrates. Training will be given in boat handling, sampling, taxonomy, analytical and statistical modelling techniques.
Related Publications Hendry, K, Webb, S F & White, K N (1993) Water quality and urban regeneration: a case study of the central Mersey basin. In: Urban Waterside Regeneration: Problems and Prospects. (ed: White, K N, Bellinger, E G, Saul, A J Symes, M & Hendry, K) Ellis Horwood, Chichester, pp.271-282. Williams, A E, Waterfall, R J, White, K N & Hendry, K (2010) Manchester Ship Canal and Salford Quays: industrial legacy and ecological restoration. In: Ecology of Industrial Pollution (ed: Batty, L C & Hallberg, K B). Cambridge University Press, 276-308 Fee Band This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants.

PhD Project : Understanding regulated activation of the Notch receptor, a key process for stem cell maintenance and cell differentiation. (Faculty of Life Sciences - The University of Manchester)

Wed, 18 Aug 2010 13:14:29 +0100

Understanding regulated activation of the Notch receptor, a key process for stem cell maintenance and cell differentiation. Principal investigator(s): Dr Johanna Avis Funding: Project available for individuals with self arranged funding. Subject Areas Biochemistry Bioinformatics Biomolecular Sciences Developmental Biology Gene Expression Molecular Biology Molecular Cancer Studies Stem Cell Research Structural Biology Description Notch receptors are transmembrane glycoproteins that are of fundamental importance in multiple cell-fate decisions, such as occur during stem cell maintenance and cell differentiation. Notch receptors interact with membrane-tethered ligands (Delta and Jagged) presented on neighbouring cells, resulting in downstream events that lead to control over the receiving cell's differentiation programme. Dysregulation of Notch has been implicated in a myriad of disease states, including cancers. To achieve a signal, the Notch receptor must undergo three proteolytic cleavage events that enable release of the Notch intracellular domain into the cytosol, whereupon it translocates to the nucleus to act as a transcription factor. The second proteolytic cleavage, at a site 'S2', is key to Notch activation, triggered by ligand binding. The crystal structure of the Notch heterodimerisation (HD) domain, together with the adjacent LNR domain reveals that this S2 site is normally buried and that Notch is thus autoinhibited. This S2 site needs to be unmasked to activate Notch. We will explore the hypothesis that ligand binds to the extracellular domain of Notch and then exerts sufficient force (upon its endocytosis) to cause exposure of the S2 site through conformational change. Together with physical scientists, we will thus conduct an investigation into the mechanical stability of the Notch LNR and HD domains. We have already produced recombinant Notch LNR and HD domains and subjected single molecules to mechanical force, observing unfolding of individual domains. This PhD will continue the single molecule work, using atomic force microscopy to establish whether mechanical unfolding can expose the S2 site. The work can extend to analysis of Notch mechanical unfolding and activation on live cells, ideally subsequently tracking the translocation of the intracellular domain to the nucleus (new method development). The work can also include a computational analysis for modelling of structural changes to the Notch receptor. Related Publications Hansson EM, Lendahl U, Chapman G (2004) Notch signaling in development and disease . Semin Cancer Biol. 14, 320-8. Louvi A, Arboleda-Velasquez JF, Artavanis-Tsakonas S. (2006) CADASIL: A critical look at a Notch disease. Dev Neurosci. 28, 5-12 Gordon WR, Vardar-Ulu D, Histen G, Sanchez-Irizarry C, Aster JC, Blacklow SC. (2007) Structural basis for autoinhibition of Notch . Nat Struct Mol Biol. 14, 295-300. Malecki MJ, Sanchez-Irizarry C, Mitchell JL, Histen G, Xu ML, Aster JC, Blacklow SC. (2006) Leukemia-associated mutations within the NOTCH1 heterodimerization domain fall into at least two distinct mechanistic classes. Mol Cell Biol. 26, 4642-51. Vogel V (2006) Mechanotransduction involving multimodular proteins: converting force into biochemical signals. Annu. Rev Biophys Biomol Struct 35, 459-488. Fee Band This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants.

PhD Project : Structural analysis of protein synthesis factor complexes using electron cryo-microscopy (Faculty of Life Sciences - The University of Manchester)

Wed, 18 Aug 2010 13:12:48 +0100

Structural analysis of protein synthesis factor complexes using electron cryo-microscopy Principal investigator(s): Dr Graham Pavitt , Dr Alan Roseman Funding: Project available for individuals with self arranged funding. Subject Areas Biochemistry Biotechnology Gene Expression Molecular Biology Structural Biology Description Structural studies of proteins greatly enhance our understanding of molecular function and mechanisms. We have been studying the molecular mechanisms of protein synthesis and its control in eukaryotic cells. This multistep process relies on a dynamic series of protein-protein and protein-RNA interactions necessary to assemble correctly ribosomes, mRNAs, tRNAs and mRNA. This project will use recombinant protein expression systems to purify specific protein complexes and then use electron microscopy techniques to obtain images that can be used to gain insight into the structures of these molecules that are critical for protein synthesis and its control, which are important for human health and disease.
The specific protein complexes to be studied here are the nucleotide exchange protein called eIF2B, a multisubunit complex which interacts with a second multisubunit protein, a GTP-binding factor, called eIF2 to regulate protein synthesis in all cells. Mutations in eIF2B cause a genetically inherited brain disease. Regulation of eIF2B activity is critical for a wide variety of cues, including: nutritional responses, stress, fighting viral infections, and long-term memory.
Individual protein complexes and co-complexes will be generated by purifying protein complexes from yeast cells engineered to overexpress the target proteins. Samples will be prepared by the negative stain or cryo techniques, and images collected on the transmission electron microscope. Structures of the complexes will be reconstructed in three dimensions.
Analysis of the complex and co-complexes will provide new information to assign the positions of subunits and build a 3D model. Where possible, models of individual subunits generated from Xray crystallography and/or homology modelling will be fitted by density docking into the three dimensional EM maps. Known disease state mutations will then be mapped onto the structures. These experiments will allow deeper understanding and provide insight into the structure/functions of these factors.
Related Publications Martin D. Jennings and Graham D. Pavitt. (2010). eIF5 has GDI activity necessary for translational control by eIF2 phosphorylation. Nature, 465(7296), 378-381. Pavitt GD, Proud CG. (2009). Protein synthesis and its control in neuronal cells with a focus on vanishing white matter disease. Biochem Society Transactions, 37, 1298-1310. Mohammad-Qureshi SS, Haddad R, Hemingway EJ, Richardson JP, and Pavitt GD (2007) Critical contacts between the eukaryotic initiation factor 2B (eIF2B) catalytic domain and both eIF2beta and 2gamma mediate guanine nucleotide exchange. Molecular and Cellular Biology 27(14): 5225-34. Roseman, A.M., Berriman, J.A., Wynne, S.A., Butler, P.J.G. & Crowther R.A. (2005). A structural model for hepatitis B virus core maturation. Proc. Natl. Acad. Sci. USA 44, 15821-15826. Roseman, A.M., Chen, S., White, H., Braig, K. & Saibil, H.R. (1996). The chaperonin ATPase cycle: mechanism of allosteric switching and movements of substrate-binding domains in GroEL. Cell 87, 241-251. Fee Band This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants.

PhD Project : Stem cells for the treatment of diabetes (Faculty of Life Sciences - The University of Manchester)

Wed, 18 Aug 2010 13:12:28 +0100

Stem cells for the treatment of diabetes Principal investigator(s): Dr Karen Cosgrove Funding: Project available for individuals with self arranged funding. Subject Areas Channels & Transports Developmental Biology Physiology Stem Cell Research Description The potential of transplantation-based therapy for the cure of diabetes is currently limited by the availability of transplantable material from human donors. This problem may be overcome by deriving new insulin-secreting cells from human embryonic stem (ES) cells, adult stem cells or induced pluripotent stem cells. The aim of this project is to establish novel techniques to grow and differentiate human stem cells towards insulin-secreting cells using 3-dimensional approaches to cell culture. It is important to relate the function of newly-derived insulin-secreting cells to those of mature human ?-cells and this will be carried out by characterising the details of glucose-induced insulin release and responses of cells to a number of physiologically-relevant agents. The PhD student will have access to a range of different stem cell types including adult stem cells and, where appropriate, human embryonic stem cells. Techniques used during the project will include advanced cell culture methodologies, immunofluorescence microscopy, RT-PCR, quantitative PCR, Flow cytometry including FACS, live cell-imaging techniques and enzyme-linked immunosorbent assays.
Related Publications Liew, C.G.; Shah, N.N;Briston, S.J.; Khoo, C.P.; Shepherd, R.M.; Dunne, M.J.; Moore, H.D.; Cosgrove K.E. and Andrews, P.W.A. (2008) Enhanced beta-cell lineage differentiation following stable expression of Pax4 in human embryonic stem cells. PLOS One. 3(3) e1783. doi:10.1371/journal.pone.0001783. Liew, C.G.; Moore, H.; Ruban, L.; Shah, N.; Cosgrove, K., Dunne, M.J. and Andrews, P. (2005) Human embryonic stem cells: possibilities for human cell transplantation. Ann Med. 37(7): 521-532.
Fee Band This project has a Band 3 fee. Details of different fee bands are available for UK/EU or International applicants.

PhD Project : New drug targets for epilepsy (Faculty of Life Sciences - The University of Manchester)

Wed, 18 Aug 2010 13:12:10 +0100

New drug targets for epilepsy Principal investigator(s): Professor Richard Baines Funding: Project available for individuals with self arranged funding. Subject Areas Animal Biology
Channels & Transporters
Genetics
Integrative Neurobiology & Behaviour
Molecular & Cellular Neuroscience
Neuroscience
Pharmacology
Physiology
Systems Neuroscience
Description Epilepsy is a common syndrome that affects ~1% of the global population. Although anti-epileptic drugs (AEDs) are available, roughly one-third of sufferers are insensitive. Even for those that respond, drug treatment is only palliative. There is, therefore, a critical need for new drugs, based on novel targets, with the ultimate aim of providing a cure for those individuals that exhibit idiopathic epilepsies (i.e. heritable forms). The fruitfly Drosophila offers tractable genetics and genotypes that readily and reliably display reduced seizure thresholds. Seizures in these so-called 'bang-sensitive' mutants exhibit sufficient parallels with human epilepsy to implicate the underlying neuronal abnormalities are highly similar. We have recently completed a first detailed study of neuron signalling in bang-sensitive mutants and, remarkably, have shown that treatment of mated females with the AED phenytoin fully prevents seizure in their larval progeny. This result provides a first real indication that at least some forms of epilepsy arise as a consequence of incorrect neural development. Moreover, our results suggest that early drug intervention, during embryonic development, may represent a highly effective method to control (and perhaps even eliminate) epilepsy in humans. The available project will fully test this hypothesis by attempting to both reduce and induce seizures in wild type and bang-sensitive mutants through manipulation of embryonic neural development. You will join a large and active group and will receive training in a wide range of techniques, including but not limited to: Drosophila genetics, electrophysiology (whole cell patch clamp), confocal microscopy and analysis of seizure-behaviour. Further information can be found at: http://personalpages.manchester.ac.uk/staff/Richard.Baines/default
Related Publications Reynolds, E.R., et al., (2004) Treatment with the antiepileptic drugs phenytoin and gabapentin ameliorates seizure and paralysis of Drosophila bang-sensitive mutants. J Neurobiol, 58(4): p. 503-13. Song, J. and M.A. Tanouye. (2008) From bench to drug: human seizure modeling using Drosophila. Prog Neurobiol, 84(2): p. 182-91. Muraro NI, Baines RA. (2008) Drosophila melanogaster in the study of epilepsy. SEB Exp Biol Ser 60:141-160.
Fee Band This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants.

PhD Project : Regulation of inflammatory cells in injured tissue (Faculty of Life Sciences - The University of Manchester)

Wed, 18 Aug 2010 13:10:17 +0100

Regulation of inflammatory cells in injured tissue Principal investigator(s): Dr Kimberly Mace Funding: Project available for individuals with self arranged funding. Subject Areas Biomolecular Sciences Cell Biology Developmental Biology Gene Expression Immunology Molecular Biology Stem Cell Research Description Using GFP bone marrow chimeras, we are analyzing the behaviour of inflammatory cells in different wound environments, such as chronic wounds and acute (normal) wounds. Sustained expression of Hoxa3 during tissue repair and regeneration reduces inflammation and accelerates healing, however, it is unclear if this is direct or indirect (whether Hoxa3 function is required in the wound resident cells, the inflammatory cells, or both). We would like to better understand the regulation of inflammatory cell gene expression in response to injury. Current projects include: the development of an in vitro co-culture model system which will allow fast and efficient assays of inflammatory cell behaviour under a variety of conditions the development of fluorescence activated cell sorting (FACS) and reporter assays to study populations of inflammatory cells isolated form wounds at different time points, as well as from chronic v acute wounds Related Publications Mace KA, Hansen SL, Myers C, Young DM, Boudreau N, (2005) HOXA3 induces cell migration in endothelial and epithelial cells promoting angiogenesis and wound repair. Journal of cell science 118(Pt 12): 2567-77. Fee Band This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants.

PhD Project : The role of CFTR in bicarbonate secretion by airway epithelial cells (Faculty of Life Sciences - The University of Manchester)

Wed, 18 Aug 2010 13:09:57 +0100

The role of CFTR in bicarbonate secretion by airway epithelial cells Principal investigator(s): Dr Martin Steward Funding: Project available for individuals with self arranged funding. Subject Areas Channels & Transports Physiology Description Cystic fibrosis (CF) is the most common, lethal, inherited disease in the Caucasian population. Patients with CF suffer from recurring infections of the airways as a consequence of the failure of epithelial cells to secrete electrolytes and water. This is due to mutations in the membrane transport protein CFTR (cystic fibrosis transmembrane conductance regulator). Although CFTR is known to function as a chloride-selective ion channel, it also appears to have a key role in the secretion of bicarbonate ions. Recent work has revealed that CFTR may promote bicarbonate secretion by activating members of the newly-discovered SLC26 family of anion exchangers. The aim of this project is to identify, localize and characterize the SLC26 anion exchangers expressed in the Calu-3 cell line derived from secretory cells in the human airways. Techniques will include RT-PCR, immunoblotting, immunohistochemistry, transfection, Ussing chamber techniques and microfluorometry. Related Publications Steward MC, Ishiguro H & Case RM (2005) Mechanisms of bicarbonate secretion in the pancreatic duct. Annual Review of Physiology 46, 14.1-14.33 Fee Band This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants.

PhD Project : Development of high-throughput screens for novel cystic fibrosis drugs. (Faculty of Life Sciences - The University of Manchester)

Wed, 18 Aug 2010 13:09:38 +0100

Development of high-throughput screens for novel cystic fibrosis drugs. Principal investigator(s): Professor Bob Ford Funding: Project available for individuals with self arranged funding. Subject Areas Biochemistry Channels & Transporters Molecular Biology Structural Biology Description Cystic fibrosis is the most common human inherited disease, affecting ~1 in 4000 births. Drugs targeted to the mutated protein (CFTR) are urgently needed. This project will be aimed at the development of high-throughput drug screening assays for CFTR. The project will involve the expression of the recombinant wild-type and mutated CFTR proteins in microbial systems, followed by their purification and biophysical characterisation. The proteins will be reconstituted into lipid vesicles and their activity checked using a variety of biochemical assays. Finally, fluorescent reporter assays will be developed to monitor the activity of the recombinant proteins in the presence of drugs. In the latter stages, the student will be involved in the translation of the assays to a standard 96-well format for high-throughput screening. This project is linked to Cystic Fibrosis Foundation Therapeutics Inc. (USA) which is sponsoring the research in the Ford laboratory. Related Publications Rosenberg, M. F., A. B. Kamis, et al. (2004). "Purification and crystallization of the cystic fibrosis transmembrane conductance regulator (CFTR)." J Biol Chem 279(37): 39051-7. Awayn, N. H., M. F. Rosenberg, et al. (2005). "Crystallographic and single-particle analyses of native- and nucleotide-bound forms of the cystic fibrosis transmembrane conductance regulator (CFTR) protein." Biochem Soc Trans 33(Pt 5): 996-9. Zhang, L., L. A. Aleksandrov, et al. (2009). "Architecture of the cystic fibrosis transmembrane conductance regulator protein and structural changes associated with phosphorylation and nucleotide binding." J Struct Biol 167(3): 242-51. Kos, V. and R. C. Ford (2009). "The ATP-binding cassette family: a structural perspective." Cell Mol Life Sci 66(19): 3111-26.
Fee Band This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants.

PhD Project : New drug targets for epilepsy (Faculty of Life Sciences - The University of Manchester)

Wed, 18 Aug 2010 13:09:22 +0100

New drug targets for epilepsy Principal investigator(s): Dr Richard Baines Funding: Project available for individuals with self arranged funding. Subject Areas Animal Biology
Channels & Transporters
Genetics
Integrative Neurobiology & Behaviour
Molecular & Cellular Neuroscience
Neuroscience
Pharmacology
Physiology
Systems Neuroscience
Description Epilepsy is a common syndrome that affects ~1% of the global population. Although anti-epileptic drugs (AEDs) are available, roughly one-third of sufferers are insensitive. Even for those that respond, drug treatment is only palliative. There is, therefore, a critical need for new drugs, based on novel targets, with the ultimate aim of providing a cure for those individuals that exhibit idiopathic epilepsies (i.e. heritable forms). The fruitfly Drosophila offers tractable genetics and genotypes that readily and reliably display reduced seizure thresholds. Seizures in these so-called 'bang-sensitive' mutants exhibit sufficient parallels with human epilepsy to implicate the underlying neuronal abnormalities are highly similar. We have recently completed a first detailed study of neuron signalling in bang-sensitive mutants and, remarkably, have shown that treatment of mated females with the AED phenytoin fully prevents seizure in their larval progeny. This result provides a first real indication that at least some forms of epilepsy arise as a consequence of incorrect neural development. Moreover, our results suggest that early drug intervention, during embryonic development, may represent a highly effective method to control (and perhaps even eliminate) epilepsy in humans. The available project will fully test this hypothesis by attempting to both reduce and induce seizures in wild type and bang-sensitive mutants through manipulation of embryonic neural development. You will join a large and active group and will receive training in a wide range of techniques, including but not limited to: Drosophila genetics, electrophysiology (whole cell patch clamp), confocal microscopy and analysis of seizure-behaviour. Further information can be found at: http://personalpages.manchester.ac.uk/staff/Richard.Baines/default
Related Publications Reynolds, E.R., et al., (2004) Treatment with the antiepileptic drugs phenytoin and gabapentin ameliorates seizure and paralysis of Drosophila bang-sensitive mutants. J Neurobiol, 58(4): p. 503-13. Song, J. and M.A. Tanouye. (2008) From bench to drug: human seizure modeling using Drosophila. Prog Neurobiol, 84(2): p. 182-91. Muraro NI, Baines RA. (2008) Drosophila melanogaster in the study of epilepsy. SEB Exp Biol Ser 60:141-160.
Fee Band This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants.

PhD Project : Towards new biocatalysts and biofuels: manipulating enzymes from structural and mechanistic perspectives (Faculty of Life Sciences - The University of Manchester)

Wed, 18 Aug 2010 13:03:30 +0100

Towards new biocatalysts and biofuels: manipulating enzymes from structural and mechanistic perspectives Principal investigator(s): Professor Nigel Scrutton Funding: Project available for individuals with self arranged funding. Subject Areas Biomolecular Sciences Description Enzymes have the potential to contribute extensively in white biotechnology, for example in industrial biocatalysis and the generation of novel biofuels. We are developing deep understanding of the structures and mechanisms of enzyme systems with a view to targeting enzymes for applications in novel biocatalysis and biofuels applications. Work in the group involves high throughput evolution and structure-based rational design of enzyme systems across a broad spectrum of disciplines involving enzyme biophysics (spectroscopy and structure determination), chemical biology, kinetics, robotic screening of enzyme variants and library construction, rational design through modelling and mutagenesis. We have state-of-the-art facilities for high throughput laboratory based enzyme evolution and infrastructure for mechanistic analysis of enzyme systems. The PhD programme is interdisciplinary and would suit a student with interests in chemistry or biochemistry. The project will provide excellent training in modern mechanistic and structural enzymology in a large and well-funded research group working generally in the area of biological catalysis. Related Publications Biocatalysis with thermostable enzymes: structure and properties of a thermophilic 'ene'-reductase related to Old Yellow Enzyme (2009). Adalbjörnsson, B. V., Toogood, H.S., Fryszkowska, A., Pudney, C. R., Jowitt, T. A., Leys, D. & Scrutton, N. S. ChemBioChem. 11, 197-207
Asymmetric reduction of activated alkenes by pentaerythritol tetranitrate reductase: specificity and control of stereochemical outcome by reaction optimisation (2009). Fryszkowska, A., Toogood, H., Sakuma, M., Gardiner, J. M., Stephens, G. M. & Scrutton, N. S. Adv. Synth. Catal. 351, 2976-2990
Structure-based insight into the asymmetric bioreduction of the C=C double bond of a-b-unsaturated nitroalkenes by pentaerythritol tetranitrate reductase (2008). Toogood, H. S., Fryszkowska, A., Hare, V., Fisher, K., Roujeinikova, A., Leys, D., Gardiner, J. M., Stephens, G. M. & Scrutton, N. S. Adv. Synth. Catal. 350, 2789-2803.
Fee Band This project has a Band 1 fee. Details of different fee bands are available for UK/EU or International applicants.

PhD Project : Analysis of mitochondrial regulators of apoptosis by mass spectrometry (Faculty of Life Sciences - The University of Manchester)

Wed, 18 Aug 2010 12:18:20 +0100

Analysis of mitochondrial regulators of apoptosis by mass spectrometry Principal investigator(s): Dr Andrew Gilmore Funding: Project available for individuals with self arranged funding. Subject Areas Biochemistry Cell Biology Cell Matrix Research Molecular Biology Molecular Cancer Studies Description Apoptosis is s genetically defined mechanisms for programmed cell death. Once initiated, apoptosis deletes unwanted or damaged cells, a process that is completed within a few minutes. Proper regulation of this process is essential, not only for ensuring that damaged cells die, but also to prevent unwanted apoptosis of healthy cells. Indeed, defects in apoptosis regulation are associated with too much cell death, seen in neurodegenerative conditions, and too little, associated with cancer. The Bcl-2 family of proteins function on mitochondria to regulate apoptosis. Our recent work has identified a large, multi-protein complex on mitochondria that regulates apoptosis by controlling activation of the pro-apoptotic Bcl-2 family protein, Bax. This project will identify the proteins within this complex and determine how they regulate Bax and cell death. The project will provide training in a broad range of state of the art methods, using our well-equipped Bimolecular analysis facility. You will use a biochemical/mass-spectrometry approach to isolate and identify components of the complex from mitochondria. Following identification of components of the complex, you will characterise their function using a variety of molecular approaches, including siRNA, live fluorescent cell microscopy and site directed mutagenesis. Related Publications Gilmore, A.P., Owens, T.W., Foster, F.M. & Lindsay, J (2009). How adhesion signals reach a mitochondrial conclusion--ECM regulation of apoptosis. Current Opinion in Cell Biology, 21: 654-61. Owens, T.W., Valentijn, A.J., Upton, J., Keeble, J., Zhang, L., Lindsay, J., Zouq, N.K. & Gilmore, A.P (2009). Apoptosis commitment and activation of mitochondrial Bax during anoikis is regulated by p38MAPK. Cell Death and Differentiation, 16(11):1551-62 Valentijn A J, J-P Upton, N Bates and A P Gilmore. (2008). Bax targeting to mitochondria occurs via both tail anchor-dependent and -independent mechanisms. Cell Death and Differentiation. 15(8):1243-54 Valentijn AJ, Upton JP, Gilmore AP. (2008). Analysis of endogenous Bax complexes during apoptosis using blue native PAGE - implications for Bax activation and oligomerisation. The Biochemical Journal. 412(2):347-57 Upton JP, Valentijn AJ, Zhang L, Gilmore AP. (2007). The N-terminal conformation of Bax regulates cell commitment to apoptosis. Cell Death and Differentiation, 149, 932-942 Fee Band This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants.

PhD Project : Analysis of Transcription Factor Activity in Stem Cells and Leukaemia (Faculty of Life Sciences - The University of Manchester)

Wed, 18 Aug 2010 12:18:19 +0100

Analysis of Transcription Factor Activity in Stem Cells and Leukaemia Principal investigator(s): Dr Marija Krstic-Demonacos Funding: Project available for individuals with self arranged funding. Subject Areas Biochemistry Bioinformatics Gene Expression Molecular Biology Molecular Cancer Studies Pharmacology Stem Cell Research Description Human malignancies such as leukemia and lymphomas are the common cancer in children and within first 10 leading causes of cancer related deaths in adults. One of the main treatments of this cancer includes glucocorticoid hormones. Side effects and resistance to glucocorticoid based therapy are frequently diagnosed and one of the reasons that effective treatment of these diseases has not been developed so far. The mechanism by which glucocorticoid hormones mediate their therapeutic effect is by inducing programmed cell death through the intracellular receptor called glucocorticoid receptor (GR). The aim of this research is to understand the events through which glucocorticoid hormones exert their pharmacological effects by inducing apoptosis in leukaemia, to improve the available treatments and develop novel pharmacologically beneficial approaches. In particular this study will identify the specific GR target genes that control apoptosis in cancer and in haematopoietic stem cells.
Fee Band This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants.

PhD Project : Biogenesis of mitochondrial protein: import, folding, assembly and function (Faculty of Life Sciences - The University of Manchester)

Wed, 18 Aug 2010 12:18:16 +0100

Biogenesis of mitochondrial protein: import, folding, assembly and function Principal investigator(s): Dr Hui Lu Funding: Project available for individuals with self arranged funding. Subject Areas Biochemistry Biomolecular Sciences Cell Biology Molecular Biology Organelle Function Structural Biology Description Mitochondrion, a vitally important organelle, plays crucial roles in many biological processes (e.g. cell growth and death) and is implicated in several human diseases and aging process. Understanding the molecular mechanism of mitochondria biogenesis is a major challenge in biology. Protein import is essential for the biogenesis of mitochondria, because almost all mitochondrial proteins are synthesized in the cytosol and have to be imported into mitochondria. It has been shown that mitochondrial proteins are imported in unfolded forms through well regulated import pathways and mediated by translocase complexes. Consequently, effective protein folding and complex formation within mitochondria are crucial for their function. Thus, protein import, folding and protein-protein interactions are fundamentally important processes for biogenesis of mitochondria. Research in my lab is focusing on understanding the molecular mechanism of biogenesis and function of mitochondrial intermembrane space proteins. Using Tim9 and Tim10 as model proteins, we have made several important findings and contributions to this currently very hot research field. A wide range of well-defined biophysical techniques, as well as biochemical and biological assays have been established in the lab, which will be used to comprehend the structural and functional mechanism of interactions between Tim9/Tim10 and functionally related downstream proteins, such as Mia40, AAC and/or Hot13.
Related Publications Wiedemann, N., Frazier, A. E. & Pfanner, N. (2004). The protein import machinery of mitochondria. J Biol Chem 279, 14473-6. (Review) Hell, K. (2008). The Erv1-Mia40 disulfide relay system in the intermembrane space of mitochondria. Biochim Biophys Acta 1783, 601-9. (Review) Ivanova, E. & Lu, H. (2008). Allosteric and electrostatic protein-protein interactions regulate the assembly of the heterohexameric Tim9-Tim10 complex. J Mol Biol 379, 609-16. Lu, H. et al. (2004). Functional TIM10 chaperone assembly is redox-regulated in vivo. J Biol Chem 279, 18952-8. Morgan, B. & Lu, H. (2008). Oxidative folding competes with mitochondrial import of the small Tim proteins. Biochem J 411, 115-22.
Fee Band This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants.