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PhD Studentships

For additional information on any of these studentships, please contact the supervisor concerned.
To apply, please use the postgraduate Direct Applications Portal.

This is page one of two.  Page two.

There is a possibility that these projects may be DEL funded (Department for Employment and Learning Studentships).  For further information on eligibility for funding, please visit the DEL website.

The closing date for applications was: 14 January 2013.

Title:  Plant pathogenic nematodes: disrupting social communication and host location to protect plant crops
Supervisors:
 Professor Aaron Maule,  Dr Johnathan Dalzell and Dr Colin Fleming.

Background
Plant parasitic nematodes are serious pathogens of plants globally, with estimated losses to plant crop production exceeding $118 billion/year.  Cyst and root knot nematodes are endoparasites that compromise numerous major food crop production systems and undermine global food security.  The environmentally toxic nematicides used to control them have been withdrawn, undermining control and necessitating the discovery and implementation of novel control strategies.  The infective stage parasites hatch within the soil and rely on sensory cues from host plants to orientate towards, locate and invade host plant roots.  Much of the damage done by plant pathogenic worms is during the root-invasion process which facilitates the entry of other fungal and bacterial pathogens.  We have developed robust gene silencing methods for neuronal targets and have identified sensory function effectors involved in the orientation behavior of infective stage parasites. This project would build on this work by interrogating sensory function in these plant pathogens more broadly and validating new control targets that are critical to host plant location and/or invasion.

Research Aims
The overarching aim is to dysregulate normal plant pathogenic behavior within the soil such that they are unable to orientate towards and locate host plant roots; there are three specific aims:

  1. Exploit the new cyst nematode genome sequence to identify proteins involved in sensory function and social communication through homology searches with known sensory effectors from Caenorhabditis elegans.
  2. Candidate sensory effectors from cyst nematodes will be silenced using RNA interference and impact on pathogen behavior monitored.
  3. The ability of potential control target manipulation to protect host plants from infection will be used to validate new control targets for plant pathogenic nematodes.

Title:  Anaerobic mitochondrial metabolism and bioenergetics - a choke point for disease control?
Supervisors:
 Dr Alexander Galkin and Professor Aaron Maule.

Background
Potentially, mitochondria can perform electron transport chain-associated phosphorylation processes in the absence of oxygen.  This process, unlike aerobic respiration, is characterised by the ability to catalyse mitochondrial ATP synthesis using the so-called NADH:fumarate reductase pathway.  Mitochondria of cancer cells associated with hypovascular tumors also maintain ATP-production in the absence of oxygen.  It has been found that some cancer cells rely on the mitochondrial NADH:fumarate reductase system to generate ATP.  Such a metabolic system is different from that in aerobic cells and represents a promising novel target for anticancer and anti-pathogen chemotherapy.

The techniques employed may include cell fractionation, enzymology, respirometry, purification of membrane proteins, mass spectrometry and iRNA.

Research Aims
This project will aim to:

  1. Characterize catalytic and structural differences between mitochondria from aerobic and anaerobic organisms using isolated mitochondrial membranes and/or intact cells/tissues.
  2. Assess the impact of a number of specific inhibitors of the enzymes involved in the associated metabolic pathways to enable identification of the most sensitive targets.
  3. Once identified, these targets will be validated in selected endoparasitic helminths using RNA interference and bioassay screens to gauge the impact of knockdown on worm biology.

This project has the potential to discover and validate new drug targets in parasites and could also pave new avenues for anticancer interventions.

Title:  Phosphorus responsive transcriptome in grasses
Supervisors:
 Professor Andrew Meharg and Dr Caroline Meharg (née Reiff).

Background
Development of crops adapted to phosphorous limiting conditions is both economically and ecologically important and aids future food security.  Wild grasses are genetically very closely related to grain crops and have traits useful to overcoming phosphorus deficiency.  The common wild grass H. lanatus exhibits a polymorphism in phosphorus utilization, one phenotype being phosphorus fertilizer responsive, the other non-responsive.

We have already extracted RNA from 5 genovars of each phenotype, in a factorial experiment with high and low phosphorus and sequenced the cDNA using 454 and Illumina technology, assembled and annotated a common reference transcriptome from the 454 data and mapped the Illumina reads to the reference transcriptome for identification of differentially expressed genes.
It is proposed that the studentship:

  • Assemble transcriptomes specific to each genovar
  • Mine/explore transcriptome Assemblies for isoform sequence variants/ expression levels
  • Mine public databases for homologous genes/ pathways
  • Investigate gene function of non-annotated genes using bioinformatics approaches such as pattern matching/ motif search
  • Verify identified sequence isoforms with RT-PCR and Sanger sequencing
  • Perform chemical assays to underpin biology

We expect to build a knowledge base of genes/isoforms involved in adaptation to phosphorous limiting conditions.

This project would suit students with either biological or computational background.

Research Aims

  • To mine the 454 transcriptome assembly and RNAseq data as well as pubic databases for pathways/genes/isoforms involved in adaptation to phosphorous limiting conditions
  • To perform genovar specific transcriptome assemblies for a more detailed analysis and identification of genes/isoforms involved in adaptation to phosphorous limiting conditions
  • To design primers for genes/isoforms identified
  • To verify identified genes/isoforms in each genovar using RT-PCR and Sequencing
  • To perform chemical assays to underpin the biology

Title:  Drug Target Identification and Validation in Nematode Parasites
Supervisors:
 Dr Angela Mousley,  Professor Aaron Maule and Dr Nikki Marks.

Background
Control of livestock-parasitic disease is becoming increasingly difficult to achieve due to the rapid increase in resistance of parasites to the currently available broad-spectrum drugs, including those most commonly used to treat nematode infections.  Sustained control of livestock nematode parasites will ultimately depend on the development of vaccines and/or drugs with novel modes of action that are not immediately threatened by resistance.  The nematode nerve-muscle (neuromuscular) system is a proven drug target with the majority of current anthelmintics acting on this system.  The chemical complexity of the nematode nervous system highlights the likelihood of the identification of other drug target candidates that are currently unexploited.  This project aims to identify and validate novel neuronal-based drug target candidates in parasitic nematodes of livestock including those within the classical transmitter and neuropeptide signalling systems.  Validation of selected neuronal-based drug target candidates will be achieved through the application of RNA interference (gene silencing).  Since its discovery in C. elegans, several nematode species have been defined by their susceptibility to this technique including important animal parasitic nematodes (Haemonchus contortus and Ascaris suum) human parasitic nematodes (Brugia malayi), and plant parasitic nematodes (Meloidogyne incognita and Globodera pallida, amongst others).

Research Aims
1. Identify gene candidates that are expressed in the neuromuscular system which are likely to be essential to parasite viability based on the Caenorhabditis elegans knock out/RNAi databases, with the most attractive candidates being those that induce lethality in key developmental stages.
2. Establish and validate the potential of these signalling systems as drug targets by probing their function through the application of gene silencing techniques (primarily in Ascaris suum) and assessing the phenotypic impact.

Title:  High Resolution Metabolomics Methods for Investigating Alzheimer's Disease (AD): Discovering Metabolite Deficiences, Disease Biomarkers and Novel Nutritional Interventions
Supervisors:
 Dr Brian Green, Dr Stewart Graham and Professor Peter Passmore.

Background
Metabolomics is useful in studying metabolite perturbations related to disease and is potentially an extremely powerful tool for disease prediction/diagnosis.  Metabolomics is potentially more powerful than existing diagnostic tools since it considers information about many biomarkers as opposed to one single biomarker.  The full diagnostic potential of the technology has yet to be been exploited but our pilot study demonstrates the technique can predict Alzheimer’s disease (AD) in brain samples from healthy age-matched controls with 94-100% accuracy.  The lack of reliable AD biomarkers makes early detection and clinical diagnosis extremely difficult.  This PhD studentship aims to trial and validate high resolution LC-qTOF-MS metabolomics for the study of AD.  It will determine the specific disturbances in the brain metabolome that distinguishes cases of mild cognitive impairment (MCI) from AD and healthy subjects.  The technology will be applied to ‘biochemically fingerprint’ blood samples from patients attending the Memory Clinic.  There is a realistic possibility that this will uncover specific nutritional deficiencies related to AD which could be tackled by dietary supplementation/fortification or the development of ‘medicinal foods’ etc.  Furthermore the project will identify new biomarkers of AD which could be used to diagnose AD, or measure the progression/severity of this degenerative disease.

Research Aims
The present proposal will broaden and extend the use of a high resolution LC-qTOF-MS metabolomics approach developed at QUB for studying Alzheimer’s disease (AD).  There are 3 specific research questions:

  1. Can metabolite perturbations in brain/blood be used to distinguish MCI, AD and controls?
  2. What are the nutritional deficiencies that affect patients with AD?
  3. Is there a specific metabolite signature for AD, and can it measure the progression and severity of the disease?

Title:  Rapid immunodiagnostics for chemical contaminants in food and the environment
Supervisors:
 Dr Chen Situ and Professor Andrew Meharg.

Background
Food safety and quality have become global concern.  Chemical contaminants such as veterinary drugs, illegal hormones, animal growth promoters, food and feed additives are widely present in our daily foods and food commodities regardless their source and production origins.  The detrimental health effects of consumption of these foods and the subsequent economic costs to both healthcare and food industry have caused a major toll and affected many nations worldwide.  It has been recognised that the lack of rapid, reliable and sensitive detection methods may partially contribute to the current food safety problems.

In addition to conventional immunodiagnostic methods that utilise poly- or monoclonal antibodies, other potential and novel binders such as bacterial phages and aptamers have recently been explored owing to their high selectivity and ability to bind multiple targets.  These protein binders can be coupled with various biotechnology platforms for development of rapid immunodiagnostics for the detection of chemical hazards in food and environment.

Research Aims
This PhD programme aims to develop immundiagnotics for rapid detection of banned and controlled chemical substances in food and environment.  A number of approaches for the design and development of rapid diagnostic tools will be investigated.  Research tasks also include investigation of different potential binders that can be incorporated with different technological platform in various formats for assay development.

Title:  Application of metagenomic analysis for the discovery of novel lignin oxidising enzymes from pristine soils
Supervisors:
 Dr Chris Allen and Dr Leonid Kulakov.

Background
Oxidoreductase enzymes are important biocatalysts with many applications as industrial enzymes.  Our research group has been involved in the discovery of new industrial enzymes, and recently we have been developing methods that utilise metagenomic analysis to harvest novel genes for these enzymes from diverse environments.

In this research project we would like to test different strategies for the isolation, and ultimately application of novel enzymes from bacteria that are thought to be naturally used for the degradation of the natural phenols that are found in lignin. Lignin is the most abundant aromatic polymer on the planet and a useful potential feedstock for fine chemicals, pharmaceutical APIs and biofuels.  We therefore believe there will be many applications for such enzymes in industry – the biocatalysts may also have many useful properties that could help us understand the intricate nature of the global carbon cycle in the environment.

The project would be ideal for a researcher from a biochemistry/microbiology/molecular biology background with an interest in microbial ecology and/or microbial biotechnology.  The research builds upon an extensive research program that has led to over 50 related publications and attracted considerable research support.

Research Aims
The aims of the research are to:

  1. Conduct microbial ecology on pristine soils.
  2. Specifically look for novel biocatalysts - such as oxidases and oxygenases - using metagenomic methods.

Title:  Structural biology of membrane transporter proteins
Supervisors:
 Dr Chris Law and Dr John Nelson.

Background
Active transport of substances across cell membranes is crucial to many cellular and physiological processes, and is of great medical and pharmaceutical significance.  Integral membrane transporter proteins, including those that function in biological phenomena such as resistance to antibiotics and anticancer drugs, catalyse the transport process.  My laboratory welcomes applications from enthusiastic individuals for a PhD studentship to investigate the structure and molecular mechanism of a novel integral membrane transporter protein that functions in multidrug resistance, pH homeostasis and osmoregulation in pathogenic bacteria.  The work will utilize a smörgåsbord of cutting-edge techniques including X-ray crystallography and stopped-flow fluorescence spectroscopy of protein reconstituted into proteoliposomes, and will involve travel to synchrotron radiation facilities.  Full training in these and other state-of-the-art biophysical techniques will be delivered to the successful candidate.

Research Aims
To elucidate the 3-D structure and molecular mechanism of members of an important and poorly understood family of membrane transporter proteins using X-ray crystallography and a battery of other advanced biophysical methods.

Title:  Galactosemia:  from biochemical causes to therapies
Supervisors:
 Dr David Timson and Dr Kostya Panov.

Background
Galactosemia is a genetic disease resulting from mutations in genes encoding the enzymes of galactose metabolism.  Work in my laboratory has established that, in the case of the most severe forms, ie type I (galactose 1-phosphate uridylyltransferase, GALT, deficiency) and type III (UDP-galactose 4’-epimerase. GALE, deficiency), the underlying biochemical causes include reduced enzymatic activity, reduced cofactor affinity and reduced stability.  However the contributions from each of these causes varies with each specific mutation.

In this project, the student will use recombinant GALE to recapitulate a series of polymorphisms and assess the effects of these changes on the protein’s stability and activity with the aim of determining if any of these polymorphisms may result in aberrant galactose metabolism. Further studies may be carried out on novel mutations identified by clinical collaborators. In parallel, the student will test compounds identified in a virtual screen currently being carried out by collaborators in the USA for their ability to stabilise GALE:  such molecules could be the starting point for “small molecule chaperone” treatments for galactosemia.  The project will permit considerable flexibility for the student, with the opportunity to develop further research interests relating to the biochemical basis of all forms of galactosemia.

Research Aims

  1. Recapitulate GALE polymorphisms (from databases) in recombinant GALE.  Test activity, stability according to established assays.  Determine if likely to be associated with disease.
  2. Carry out similar process with novel mutations identified by clinical collaborators.
  3. Test compounds identified from virtual screen for ability to stabilize wild-type GALE and selected mutants.
  4. Test other predictions of molecular modelling using site-directed mutagenesis.
  5. Expand 1-4 to GALT and/or galactokinase as appropriate and if time permits.

Title:  The role of a dietary carcinogen (heterocyclic amines) in the development of colon cancer:  use of biomarkers and metabolomics
Supervisors:
 Dr Geraldine Cuskelly and Professor Chris Elliott.

Background
Since the late 1970s, a substantial body of research has emerged in the areas of cooking-induced mutagens/carcinogens and cancer risk.  One such group of food-derived mutagens are heterocyclic amines (HCAs).  A number of them have been classed as carcinogens but human epidemiological studies are inconclusive as to their role in carcinogenesis.  Adducted protein HCAs have been shown to be a good marker of HCA status and directly relevant as cancer markers.  However, methods currently used to measure adducts are prohibitively expensive.

This proposal sets out to quantitate adducted protein biomarker status of heterocyclic amine (HCA) exposure using immunochemical and phage display-based techniques.  Compared with current methods for measuring adducts, immunochemical techniques are significantly less expensive enabling more rapid and higher throughput.

Immunochemical methods will be used involving monoclonal antibody development, followed by development of a high-throughput sensor-based biomarker immunoassay to determine individual sample HCA-adducted protein levels (specific HCAs (MeIQx & PhiP) and proteins (albumin and haemoglobin).

Further work will explore the effect of HCA intakes/exposure in pregnant mice on cancer risk in offspring mice using adduct status and metabolomics.

  1. Develop phage display-based methods to analyse protein-adducted HCAs (focus will be made on specific HCAs (MeIQx & PhiP) and on specific proteins (albumin and haemoglobin)).
  2. These newly developed methods will be tested and validated by application to a large cross-sectional survey of adolescents, Young Hearts 2000.
  3. Assess the effect on adduct status on offspring of HCA intakes in pregnant mice and subsequent assessment of other metabolic changes using metabolomics.

Title:  Physiological processes linking dietary intervention and improved animal health status and performance
Supervisors:
 Professor Gordon Allan,  Dr Mark Mooney and Dr Michael Welsh.

Background
The utilisation of feed supplementation strategies with a view to improving the overall health status and performance of food-producing animals is of key interest both from an animal welfare and an economic perspective.  Whilst generally accepted that targeted dietary interventions can improve animal performance, the physiological mechanisms underlying such improvements is often unclear.  In this regard considerable interest has centered on the potential impact of diet on gut metabolism and the processes by which such interactions may directly or indirectly modulate animal health and productivity.  There is therefore a clear need for research to help better understand the role of dietary supplementation in improving animal performance and husbandry with a view to better informing the development of new feed formulations and diet strategies.  With ongoing advances in analytical technologies there has been an increased focus on the use of protein and metabolite profiling tools to quantify temporal changes in biological responses to dietary interventions.  This project will apply proteomic and metabolomic techniques to examine in vitro and in vivo cellular and metabolic responses to dietary constituents.  Through completion of this project successful candidates will develop new research skills spanning a range of interdisciplinary fields, and undergo training in state-of-the-art investigative mass spectrometry analysis, metabolomics, proteomics, systems biology and bioinformatic data interpretation.

Research Aims
The research aims of the project will be to apply proteomic and metabolomic profiling tools to assess the impact of specific dietary components and nutritional supplements on gut health and overall animal performance.  A key objective will to identify specific components and metabolic pathways which can be targeted directly or indirectly through the use of dietary interventions to deliver benefits to animal health status and productivity.