PhD projects

Using structural biology tools, our goal is to understand the relationship between structure and function of selected Clostridium difficile surface associated proteins. The proposed research has profound medical significance with a long term aim on the development of drug molecules, hence providing the crucial molecular details into possibility of achieving benefits for human health.

Project description:

General: Clostridium difficile has a number of virulence factors. The pathogenic strains of Clostridium difficile produce two potent exotoxins, Toxin A and Toxin B (often called TcdA and TcdB) which induce mucosal inflammation and diarrhoea. In addition to these exotoxins, some Clostridium difficile strains produce an ADP-ribosylating binary toxin (CDT). However, the role of this toxin in disease is not fully understood. Another factor was identified by studies of the role of S-layer proteins (SLPs) in the cell wall when it was shown that the outer coat of Clostridium difficile may also play a role in increasing the adhesion of the organism to various surfaces, including the gastrointestinal lining and perhaps inanimate surfaces, thus making spore removal more difficult.

Supervisor:

• Professor K. Ravi Acharya

Loss of epithelial junctions is believed to be a key step in tumour formation and central to the maintenance of these junctions is protein trafficking. For example, our group has shown, in mammalian tissue culture cells, that tight junction membrane proteins of the claudin family are continuously being endocytosed and returned to the plasma membrane in a process called recycling (1). Perturbation of endocytic machineries can block this recycling leading to an intracellular accumulation of claudins (1,2), which might act to weaken epithelial junctions. The proposed project is to investigate mechanisms of endosomal sorting of claudins and other junctional proteins and will help to explain if a failure to control junction sorting contributes to cancer progression. This work will provide training in a range of techniques including molecular biology, cell culture, biochemical trafficking assays and confocal microscopy, equipping the student for a future research career in an academic or commercial setting.

References:

• Dukes, J.D., Fish, L., Richardson, J.D., Blaikley, E, Burns, S., Caunt C. J., Chalmers, A. D. and Whitley, P. Functional ESCRT machinery is required for constitutive recycling of claudin-1 and maintenance of polarity in vertebrate epithelial cells. (2011) Molecular Biology of the Cell 22:3192-3205.
• Dukes, J.D., Whitley, P., Chalmers, A. D. The PIKfyve inhibitor YM201636 blocks recycling of the tight junction protein claudin-1. (2011) PLoS ONE (In Press)

Supervisor:

• Dr Andrew Chalmers
• Dr Paul Whitley

Project Objectives:

1. To better understand the nature of compatible pollination in Arabidopsis thaliana through characterisation of functional interactions of pollen and stigmatic factors.
2. To identify and characterise stigmatic targets for a family of well characterised pollen-borne protein ‘ligands’

Project Description:

Successful pollination relies on a complex series of interactions between male and female reproductive cell types. This close cooperation eventually culminates in the delivery of sperm by the pollen tube to the female gametes in the embryosac . The first stage of this process involves the interaction between pollen grains and stigmatic papillar cells, where a molecular dialogue is rapidly established. This pollination ‘checkpoint’ is highly regulated such that only compatible pollen is permitted to hydrate and effect pollination.

It is becoming clear that a range of compatibility factors are involved. Work in the Doughty lab has established that several families of pollen-borne small cysteine-rich proteins (CRPs) play key roles in this process. Stigmatic targets of these ligand-like proteins are as yet unidentified and this will be a key goal of the project. Several approaches will be taken utilising both the extensive in silico resources available for Arabidopsis research along with protein-protein interaction assays and proteomic analyses. To date few stigmatic factors have been identified and a broader goal of this project will be to uncover new regulators of pollination.

Skills and training will include - general plant molecular biology techniques, microbiology, protein-protein interaction analyses, bioinformatics, knockout line analysis.

The supervisor has collaborations with Prof Simon Hiscock (University of Bristol) and Dr Jose Gutierrez-Marcos (University of Warwick) which are relevant for this project.

Note - project is suitable for UK/EU, overseas students and self-funded students.

Supervisor:

• Dr James Doughty

Complex phenotypes such as brain size, breeding behaviour, ageing patterns, life span and higher organism complexity, are some of the defining features of the human species. The molecular mechanisms underlying the evolution of these traits across mammalian lineages -including hominids- and other vertebrate taxa remain a mystery. The increased availability of genomic, next generation sequencing (RNA-seq) transcriptomic profiling and functional data for an increasing number of taxa has allowed detailed studies of gene and genome evolution. But how changes at the genome level relate to the evolution of phenotypes has been understudied. The proposed project aims to use bioinformatics tools, comparative genomics, functional genomics and gene network analysis approaches to uncover the genomic signatures at the DNA, transcriptome levels and alternative splicing levels, which underlie the evolution of complex phenotypes across mammals and other vertebrate lineages including human. Results from this project will allow a greater understanding about the evolution of key life history features at the molecular level. Moreover, findings will also provide insights into the gene networks and pathways underlying these important phenotypes in humans both in health and diseased states including cancer.

The successful candidate will join a research group of 6 PhD students and be provided with top of the range computer equipment and will have access to the servers in Dr Urrutia’s group. For more details please get in contact at: A.Urrutia@bath.ac.uk or visit http://people.bath.ac.uk/au207/

Supervisor:

• Araxi Urrutia

Imprinted genes behave unusually in that they are expressed predominantly, if not exclusively, from only one of their two alleles. Dlk1 (also known as preadipocyte factor 1) is expressed from the paternal allele while Grb10 is expressed from the maternal allele in most of the tissues where they are active. We have established that the Grb10 gene acts to suppress growth of both the embryo and placenta as Grb10 knockout mice are born approximately 30% larger than wild type littermates. In adulthood Grb10 knockout mice are lean, with increased muscle mass and reduced adipose. Conversely, Dlk1 knockout mice are small at birth and tend to accumulate excess adipose in adulthood.

Supervisor:

• Andrew Ward

Geobacillus spp have been shown to be versatile organisms for the production of ethanol from lignocellulosic wastes (Cripps et al (2009) Metabolic Engineering 398–408), including municipal solid waste. Ethanol is a natural product of energy metabolism and so it is relatively straightforward to make production an obligatory part of growth. Partitioning carbon flux between more general metabolite formation and growth is a more significant challenge but this is now being successfully addressed in model organisms such as E coli ( eg Solomon et al(2012)Metabolic Engineering 661–671). In this project we intend to apply and develop these strategies to achieve flux partition in Geobacillus spp.

Suitable for students with a first degree in Microbiology, Biochemistry or Biochemical Engineering.

Supervisor:

• Prof DJ Leak

The genus Bordetella currently comprises nine species, including several that are the causative agents of the important disease, whooping cough. Previously, we and others have generated genome sequences for five Bordetella species and used this information to establish the evolutionary histories of the main whooping cough agents, B. pertussis and B. parapertussis. We have now generated genome sequences for the remaining Bordetella species and thus stand at the point where the evolutionary relationships within the entire genus can be studies.

This project will analyse these relationships and make predictions about particular aspects of the biology of these species, with particular reference to their infection biologies. The project will combine bioinformatics approaches with experimental laboratory in which genomics informs the study of infection and immunity.

Supervisor:

• Dr Andrew Preston
• Prof. Ed Feil

Alzheimer’s disease increases in incidence with age. This clearly links the disease to changes in the brain that occur with normal aging. One of the changes that occur in the brain is an increase in number of dystrophic microglia, and this change has been associated with an increased storage of the metal iron.

This project will allow us to assess how an age related change could contribute to factors known to be important in Alzheimer’s disease. The student involved in this project will use a range of techniques to carry out the project which will include, ELISA assays of cytokines or beta-amyloid, fluorometric assays for detection of oxidative stress or luciferase assays to detect APP cleavage, western blots and other basic biochemical technques as well as extensive use of cell culture techniques and molecular biology.

By the end of the project we hope to have developed a new model of APP cleavage that takes into account age related changes in microglia. Furthermore, we will have identified and assessed the importance of two new concepts to the Alzheimer’s field. First, whether age dependent factors need to be considered in Alzheimer’s disease models, and second, whether it is the generation of beta-amyloid by a cell rather than its presence that increases the likelihood of cell death.

Supervisor:

• Prof. David R. Brown

Why construct supertrees? The development of new supertree methods and the construction of supertrees for particular clades is a burgeoning area of research in systematics. Although the rate at which phylogenomic data can be acquired is increasing exponentially, fully inclusive supermatrix phylogenies of many thousands of terminals are still some years away. Supertrees offer the means to meta-analytically synthesise published trees, simultaneously resolving conflict between them using a variety of objective optimality functions. They enable researchers to see the state of published knowledge, as well as being essential for macroevolutionary, macroecological, comparative and conservation studies that rely upon complete species phylogenies.

Why arthropods? Arthropods are the most abundant and diverse of all animal phyla containing an estimated 30 million species. They have evolved to fill virtually every habitat and exploit almost all imaginable lifestyles. Despite a century of study, there is still no consensus on their relationships, and their radiation has been the focus of debates concerning the overall pattern of the diversification of life. Arthropods are of great economic value and are also a vital component of many ecosystems. Moreover, a supertree of all arthropods has never been attempted before.

What does this project entail? The successful candidate will be part of collaborative team from the University of Bath and the Natural History Museum in London. The student will apply a variety of established and novel supertree methods to a selection of arthropod clades and benchmark their performance. They will also explore alternative supermatrix approaches and write scripts for their automation. The student will receive training in supertree methods, bioinformatics, and arthropod systematics, as well as in the use of programming languages including Perl, Python, MySQL and R.

Supervisor:

• Matthew Wills (Biology & Biochemistry, Bath)
• Araxi Urrutia (Biology & Biochemistry, Bath)
• Mark Wilkinson (Natural History Museum, London)
• Katie Davis (Biology & Biochemistry, Bath)

Polycomb group genes (PcG) genes are implicated in stem cell identity, function and differentiation. The aim of this PhD project is to analyse the consequences of knockout of the PcG genes on the stem cell compartment and its differentiation in the adult brain and in the intestine (both organs are known to possess a stem cell compartment). These studies will complement our ongoing research on Induced Pluripotent Stem (iPS) cells, PcG genes and adult stem cells. The PhD project will involve the use mouse knockouts and gene traps to investigate the role of the PcG genes in stem cells and the cell cycle, using cell biology, molecular and structure function approaches as well as new strains of reporter mice. Applicants should have a First class or high Upper Second class degree in Biochemistry/Cellular and Molecular Biology with a special interest in Development or Neurobiology. Research placements /Summer Lab experience in either of the above areas would be desirable.

Supervisor:

• Dr Vasanta Subramanian
• Professor Ravi Acharya

In many organisms males exhibit behaviours and express products in their seminal fluid that are severely deleterious for their sexual partners. It is not clear how males benefit from harm to females or how behaviours that reduce fitness are maintained by natural selection. We have recently found that, despite costs to females, frequent mating can improve the quality of offspring (Figure 1; Priest et al. 2008a) and increase levels of offspring genetic variability (Priest et al. 2007) in fruit flies. We have also found that the same male accessory gland proteins (Acps) that are harmful to females stimulate parental effects which improve the fitness of daughters (2008b). The ongoing project in the lab is to employ a systems biology approach to understand male harm of females. We will use molecular genetic, physiological and biochemical studies to test the hypothesis that stress-response pathways are responsible for parental effects on the quality and genetic variability of offspring. Based on these findings, we will develop population genetic models and life history theory to understand how harmful traits can evolve. The boundary conditions of models will be set by the results of large-scale demographic studies of the fitness consequences of mating. The project involves evolutionary theory, Drosophila genetics and molecular biology techniques.

Supervisor:

• Nick Priest

The replacement of diminishing supplies of fossil fuels, delivering fuel security and addressing man-made climate change are key global scientific and engineering challenges for the next century. This will require a substantial reduction in the dependency on petrochemical liquid fuels. Any solution must provide a fuel that is affordable, available at the required volumes, and acceptable both in terms of performance and the environmental impact of production. A promising approach is to use oleaginous microalgae grown in open raceway ponds that make use of renewable feedstocks derived from inexpensive or no-cost waste streams.

Supervisor:

• Prof. Rod J. Scott (Biology and Biochemistry)
• Dr Chris Chuck (Chemical Engineering)

The generation of amyloid β peptide (Aβ) from cleavage of the amyloid precursor protein (APP) and the subsequent aggregation of Aβ as soluble oligomers is central to the pathogenesis of Alzheimer’s Disease (AD). APP is first cleaved by β-secretase followed by γ-secretase to yield Aβ and sAPPβ in an amyloidogenic pathway, or alternatively cleaved by α-secretase followed by γ-secretase to yield a p3 fragment and neurotrophic sAPPα in a non-amyloidogenic pathway. The identification of new approaches for reducing Aβ burden either by inhibition of β/γ-secretases, stimulation of α-secretase, enhancing Aβ clearance, or by maintaining neuronal homeostasis remains a major therapeutic goal for AD particularly at its very early stages. A characteristic of AD is inflammation caused in part by the recruitment of microglial cells to Aβ containing plaques and subsequent release of inflammatory cytokines. This project will investigate the precise mechanistic links between cytokines such as TNFα, Aβ production and subsequent synaptic damage using primary cell cultures of neurones and microglia coupled to molecular approaches, biochemistry and cell imaging.

Supervisor:

• Dr Robert Williams

YAP (Yes associated protein) gene is the master organ size regulator that can expand the size of the whole organ whilst maintaining its tissue architecture when over-expressed. To achieve expansion of organ during organogenesis and regeneration, YAP needs to precisely orchestrate dynamic cell behaviors, such as differentiation of stem cells, cell proliferation and migration of differentiating cells. Mis-orchestration of cell behavior by aberrant YAP function leads to cancer.

This project will investigate how YAP orchestrates these cell behaviors during organogenesis (brain, kidney, ear, eye) and regeneration (heart and fin), and molecular mechanisms underlying these processes. Since the size of regenerating organs is regulated with respect to the size of the body, mechanisms regulating organ size need to be addressed in the context of a whole animal. Therefore, we will use zebrafish and medaka fish in which many organs regenerate as a model. These vertebrate models have a transparent body that allows observation of dynamic cell behaviour in a living animal as well as allowing genetic analysis.

Variety of techniques/skills will be acquired during the PhD: full ragnge of genetic and cellular analysis of fish embryos including transgenesis, confocal live imaging and computational 4D image analysis, in situ hybridization, immunohistochemistry. Cutting-edge live imaging analysis of cells/molecules in live embryos will be carried out by collaboration with Prof. Heisenberg (Institute of Sicience and Technology Austria, Vienna).

Supervisor:

• Dr. Makoto Furutani-Seiki
• Dr Andrew Ward

Changes in the environment are expected to challenge the persistence of populations and species. Plants will need to adapt genetically or phenotypically to new environmental conditions to persist. However, the relative importance of genetic adaptation and phenotypic plasticity (the ability of a genotype to change its phenotype according with environmental conditions) is controversial. Models show that one key aspect of persistence for non-migratory populations is how far the population mean phenotype lags behind the change in the environment. Thus, two critical parameters are needed for better prediction of species: phenotypic plasticity, and the environmental sensitivity of selection under continuous environmental variation. This project will use an outbred population of Arabidopsis thaliana (see Scarcelli & Kover 2009) to determine the genetic basis of fitness-related traits , the effect of environmental effects such as drought and temperature on the selective value of genotypes and their plastic response.

Supervisor:

• Dr. Paula X. Kover

Due to the combined demands of population growth, climate change and biofuel production, there is a very urgent need to increase agricultural output. In order to conserve natural ecosystems, any increase must be achieved by boosting yields from existing farmland. Since most crops are harvested for seed, this means increasing the total yield obtained per unit area. Seed yield has two major components: seed size and seed number. Unfortunately there is usually a trade-off between these two variables suggesting that an increase in seed size will lead to a reduction in seed number and vice versa. This project aims to use a new powerful set of recombined lines (MAGIC lines; Kover et al 2009) to fine map genes that affect size and number of seeds; and their response to environmental conditions

Supervisor:

• Dr. Paula X. Kover

Receptor tyrosine kinases are a major class of transmembrane receptors, with diverse roles in development and disease, e.g. cancer. The precise function of each kinase is distinct, yet the intracellular signalling pathways that mediate those signals are shared between all the cells. It remains a major challenge to explain how these shared pathways generate distinct outputs in a cell- and kinase-specific way.

The successful candidate will analyse the effects of different RTK proteins on both pigment cell development and the outputs of each of the secondary signalling pathways. This will allow correlation of the relationship between the balance of signalling outputs and the cellular outcome. In order to generate a comprehensive understanding of how different RTK proteins generate distinct outcomes, we wil use highly specific chemical and genetically-engineered inhibitors of the individual secondary signalling systems. Together, these studies will provide detailed insights into the crucial problem of how receptor tyrosine kinase signalling has profoundly different effects in a cell-type and receptor-type specific manner.

Supervisor:

• R. Kelsh
• J. Caunt
• S. Ward

Host switches in pathogen bacteria require a variety of adaptations. The molecular innovations allowing bacteria to infect and survive in a new host are difficult to study as often switches examined have occurred a long time ago and secondary adaptations may have taken place. Photorhabdus are bacterial symbionts of insect pathogenic Heterorhabditid nematodes which can infect a wide range of host species. The nematode worm hunts down an insect in the soil and penetrates into its open blood system. Once there the nematode releases Photorhabdus bacteria into the blood. Photorhabdus secretes a range of virulence factors that enable the bacteria to overcome innate immune response and rapidly kill the insect. Once dead, the bacteria bio-convert the insect cadaver into more bacteria, providing a suitable food source for their, now replicating, nematode partner. At this point bacteria begin to emit light although the reason for this remains obscure. When the insect resources are depleted, the juvenile nematodes “re-package” the Photorhabdus bacteria before bursting out in search of new insect prey. This “symbiosis of pathogens” is so effective that they are used as insect pest-control agents in agriculture and are economically important.

Supervisor:

• Dr Nick R. Waterfield
• Dr Araxi Urrutia

Photorhabdus are bacterial symbionts of insect pathogenic Heterorhabditid nematodes that can infect a wide range of host species. Photorhabdus produce a huge diversity of protein toxins and secondary metabolites which are used as both virulence factors and antibiotics. The nematode worm hunts down an insect in the soil and penetrates into its open blood system. Once there the nematode releases Photorhabdus bacteria into the blood. Photorhabdus secretes a range of virulence factors that enable the bacteria to overcome innate immune response and rapidly kill the insect. Once dead, the bacteria bio-convert the insect cadaver into more bacteria, providing a suitable food source for their, now replicating, nematode partner. At this point bacteria begin to emit light although the reason for this remains obscure. When the insect resources are depleted, the juvenile nematodes “re-package” the Photorhabdus bacteria before bursting out in search of new insect prey. This “symbiosis of pathogens” is so effective that they are used as insect pest-control agents in agriculture and are economically important.

Supervisor:

• Dr. Nick R. Waterfield

Social amoebae are important models for understanding conflict and cooperation during development. Free-living amoebae aggregate together and undergo development into a fruiting body (a dead stalk holding aloft a sporehead). Aggregates may contain different genotypes, leading to conflict over which genotypes are altruistic and are 'sacrificed' to produce the stalk and which contribute spores to the reproductive sporehead. As bacterial predators, the free-living amoebae are constantly at risk of infection by their prey. When infected individuals join aggregations, the presence of the pathogen may alter the outcome of conflict by determining whether cells become part of the stalk or sporehead.

This project will combine studies of bacterial predation and infection with developmental analyses of cell fate to understand how infection alters conflict between genotypes in development. Training will involve both amoeba-bacteria interaction studies, state of the art imaging, bacterial and amoeba molecular genetics and mathematical modelling.

Supervisor:

• Nick Waterfield
• Jason Wolf

Classical theory holds that selection will be weaker when populations are small. This is held to explain why our genome has large introns and large intergenic distance, this being considered to be owing to the accumulation of weakly deleterious insertions and duplications. But is selection always weaker when population sizes are small? We have recently discovered that skews in codon and amino acid usage in proximity to exon intron junctions are more pronounced when population sizes are small. This we suggest is because exonic splice enhancer motifs are needed more to correct errors in splicing when errors rates are high, which is likely to be when introns are long. This project will a) test this hypothesis in a phylogenetically controlled manner b) ask whether splice related ESE usage is predicted both by the size of introns and population size and c) ask whether it is generally the case that genomic traits associated with generalized error-proofing are under strong selection when population sizes are small. Training: use of mathematical models in an appropriate computer environment (Matlab and/or Mathematica); writing of scripts and web-crawlers (Tcl/Tk) for extraction and analysis of high-throughput data resources; R programming, MySql handling.

Supervisor:

• Laurence D. Hurst
• Araxi Urrutia

KIBRA is a key scaffold protein in the postsynaptic density (PSD), a region at the membrane of the post-synaptic neuron that is crucial for memory. KIBRA itself is important for memory and is linked to Alzheimer’s disease. Interaction with KIBRA is important for the function of PKMzeta, the key enzyme for long term memory storage. The aim of the project is to understand the mechanism of KIBRA C2 domain’s essential role in KIBRA trafficking, including investigation of the C2 domain’s Ca2+ binding properties, phospholipid selectivity, and membrane binding mechanism (C2 domains are typically, but not always, membrane association domains). NMR, isothermal titration calorimetry (ITC) and X-ray crystallography (XRC) will be used to measure Ca2+ binding properties (affinity, stoichiometry, cooperativity, occupation order of Ca2+ sites (up to three), and Ca2+-induced structural changes. Membrane binding, particularly phosphoinositide selectivity, will be studied experimentally using membrane mimics called nanodiscs. Collaborator Mark Sansom’s group will use computer simulations to study membrane penetration depth, membrane-binding geometry, lipid determinants and role of different forces in C2-membrane interaction. The student will also have the option of working for a period in collaborator Dr Joachim Kremerskothen’s group in Germany, assessing the effects of C2 mutations by live cell imaging combined with intracellular transport and cell migration assays.

Supervisor:

• Dr Stefan Bagby
• Dr Paul Whitley
• Dr Jean van den Elsen

Platelets are blood cells that help to stimulate blood clotting and that release molecules that stimulate healing. Platelet aggregation can lead to blood vessel obstruction. Anti-platelet drugs are therefore used in treating numerous conditions such as heart attack and stroke to prevent platelet aggregation. Platelet activation and aggregation is a complex process that is normally initiated by adhesion to collagen which initiates platelet cross-linking through αIIbβIII integrin binding to fibrinogen. The bacterium Staphylococcus aureus produces a protein called extracellular fibrinogen binding protein (Efb) which potently inhibits platelet aggregation and impairs wound healing, probably through its ability to bind both fibrinogen and platelets. The student will investigate whether Efb’s properties can be exploited to produce a novel anti-thrombotic agent (thrombosis is blood coagulation in a blood vessel or organ) to help treat conditions such as heart attack and stroke. The project will involve both molecular level studies (sub-cloning, protein purification and characterization, site directed mutagenesis, and design of minimal active Efb-derived peptides and small molecule Efb mimics) and cellular assays, including platelet aggregation, adhesion, thombus formation in whole blood and under flow conditions, integrin activation, fibrinogen binding and intracellular signaling cascade activation.

Supervisor:

• Dr Stefan Bagby
• Dr Giordano Pula (Pharmacy & Pharmacology)

The planet is facing interrelated challenges of food, fuel, population and climate. As the world’s sixth most important crop, cassava (Manihot esculenta) grown throughout the tropics for its starchy storage roots, can play a central role in addressing these challenges. Cassava’s desirable characteristics include drought tolerance and ability to grow on impoverished soils. Historically, cassava has been grown for food, this is especially the case in sub-Saharan Africa, but increasingly it has been grown for export as animal feed (e.g. Thailand) or starch production (China, Indonesia & Thailand). However, recently due to its efficiency at fixing CO2 into starch cassava has become a target crop for the production of biofuels (China, South America and elsewhere).

One of the principal constraints to cassava’s development and exploitation, both as a crop and commodity, is its extremely short shelf-life - the roots deteriorate within 24 – 72 hours of harvest. We have identified the major genes involved and have developed a model for this post-harvest physiological deterioration (PPD) in which reactive oxygen species (ROS)-mediated programmed cell death (PCD) is placed at the heart of the response. We are currently testing this model in transgenic cassava by modulating the ROS or PCD responses of the root; thus we can dissect the PPD response and point the way to how this problem may be controlled.

Supervisor:

• John Beeching

The pivotal molecule in long term memory storage is a protein called PKMzeta. PKMzeta acts like a conveyor belt to carry AMPA receptors to synapses. Modulation of PKMzeta activity can disrupt or enhance memory. Zeta inhibitory peptide (ZIP), for example, inhibits PKMzeta and erases all long term memories (Science 317 (2007) 951). PKMzeta over-expression enhances memory (Science 331 (2011) 1207). PKMzeta interaction with a protein called KIBRA, moreover, is crucial for PKMzeta’s conveyor belt action.

The student will use the complementary characteristics of multiple methods such as NMR, X-ray crystallography, light scattering and X-ray scattering, calorimetry and site directed mutagenesis to define details of PKMzeta structure and PKMzeta interactions with ZIP and KIBRA. The student will have the option of working for a period in collaborator Dr Joachim Kremerskothen’s group in Germany, assessing the effects of protein mutations and small molecule modulators of PKMzeta interactions by live cell imaging combined with intracellular transport and cell migration assays, and/or physiological, behavioural and memory tests.

Ultimately, better understanding of memory-related interactions such as those of KIBRA could lead to molecules that specifically disrupt individual memories, for example to treat addiction, phobias, stress and anxiety disorders, or that enhance memory to reduce age/disease/trauma-related memory decline.

Supervisor:

• Dr Stefan Bagby
• Dr Jean van den Elsen

Staphylococcus aureus is a major human pathogen, where antibiotic resistant strains are emerging worldwide (e.g. MRSA). With the costs and speed of genome sequencing decreasing rapidly, soon clinicians will be able to routinely send infectious material for rapid sequencing. What’s urgently required is a set of tools that can extract information from sequence data to help clinicians select the best treatment option for their patients and help public health officials best manage outbreaks. This project will apply molecular and cell biology (with opportunities to develop bioinformatic and mathematical modelling skills) as part of a functional genomics approach to understanding and predicting the virulence of individual S. aureus strains from their genome sequences.

Supervisor:

• Dr. Ruth Massey
• Prof. Edward Feil