Biological Sciences (PhD)

Using human disorders of keratinisation as a model, the role of differential gene expression for the function of the epidermis will be studied. Rare skin diseases are genetically and pathophysiologically heterogeneous; disturbed keratinisation based on altered keratinocyte differentiation is a major mechanism of these disorders. Using the example of autosomal recessive congenital ichthyosis, we want to study these mechanisms to understand the role of differential gene expression in the etiology of skin diseases and reveal signalling pathways involved. Keratinocytes will be analysed in primary and organotypic cell culture and their alterations characterised. Transient and permanent gene knockdown will be used to generate skin disease models, expression levels of candidate genes, especially genes involved in the epidermal lipid metabolism, will be monitored, and gene expression profiles investigated.

Self-funding applicants are welcome. In addition to tuition fees, bench fees of £5000 per annum are required for the MSc by Research and £8000 per annum for the PhD

Home/EU – for September- June 30th, for January-October 31st and Overseas for September- May 31st, for January- September 30th

• Dr Hans Hennies

Transposable elements (TEs) are genetic parasites that drive their own replication within their host’s genome. Their replication results in genomic conflict with their hosts – with elements attempting to proliferate in the genome, while hosts attempt to suppress this increase. To date TEs have mainly been studied in the multicellular animals, plants and fungi, however a small number of studies in unicellular eukaryotes indicate that TEs evolve under different evolutionary pressures in single celled organisms. This project aims to uncover evolutionary traits in TEs from unicellular eukaryotes. There will be a focus of the horizontal transfer of TEs between species, as well as the role of codon choice in the translation of TE proteins.

Self-funding applicants are welcome. In addition to tuition fees, bench fees of between £3-£15,000 per annum are required depending on the nature of the project.

Our standard University deadlines apply. Please see our Deadlines for Applications page to find out more

• Dr Martin Carr

Our understanding of eukaryotic cell biology and metabolism has predominantly been informed by studies on mammalian, yeast, and plant cells. Yet, protists by far and away account for the majority of evolutionary diversity in eukaryotes. During the last 15 years as a consequence of whole genome sequencing, surprisingly rich variations in central metabolism, metabolic compartmentalisation and organelle biogenesis have been glimpsed within protists, and thus within eukaryotes generally. Using molecular genetics, biochemical, structural biology and/or computational approaches projects studying the evolutionary cell biology of organellar metabolism in trypanosomatids and other evolutionarily divergent protists are available.

There is currently no studentship or scholarship available to support this project. Enquiries from eligible self-funding or sponsored students are welcome. In addition to the tuition fee, a bench fee of £8000 per annum will also be required.

Home/EU -June 30th/October 31st and Overseas May 31st/September 30th

• Professor Michael Ginger

A wide range of whole genome sequences are available for a number of bacteria from unique environments. This project will investigate these genomes with a specific focus on their carbohydrate biochemistry, ability to form biofilms and cellular mechanisms used to survive in extreme environments.

Self-funding applicants are welcome. In addition to tuition fees, bench fees of £3,000 per annum are required.

Home/EU -June 30th/October 31st and Overseas May 31st/September 30th

• Professor Paul Humphreys

The research in my lab is aimed at understanding normal development, metabolic physiology and aging-related diseases at molecular, cellular and physiological level. My lab is particularly interested on how glycosylation of membrane proteins regulates cell signalling in 1) neural development and regeneration and 2) metabolic physiology related to obesity, diabetes, chronic kidney disease and aging-related disorders. To this end we apply molecular and developmental genetic approaches in the nematode C. elegans in vivo and C. elegans models for human diseases (such as neuroendocrine disorders, osteo- and chondrodysplasia syndromes, metabolic disorders).

Self-funding applicants are welcome. In addition to tuition fees, bench fees of £8,000 per annum are required.

Home/EU -June 30th/October 31st and Overseas May 31st/September 30th

• Dr Tarja Kinnunen

Klotho/beta-Klotho (KLB) are transmembrane proteins that act as co-receptors for endocrine fibroblast growth factors (FGF19, -21 and -23) to activate their cognate FGF receptors (FGFRs). Klotho was originally identified as ageing-related gene when disruption of Klotho gene in mice led to phenotypes resembling ageing and shortened life-span1. We have previously shown that the function of Klotho/KLB in ageing is evolutionarily conserved in the nematode C. elegans2, which has two Klotho/KLB orthologs. C. elegans also has evolutionarily conserved insulin signalling and the role of insulin signalling in longevity and the effects of glucose on shortening lifespan were first discovered in C. elegans3. These effects are mediated via the forkhead box O (FOXO) transcription factor DAF-163. The long-lived C. elegans mutants in insulin signalling remain healthy and mobile after wild type worms look old, suggesting that the mutations not only prolong lifespan but also enhance healthspan of the aged. Aim and hypothesis The aim of this project is to understand at molecular level the cellular changes that are regulated by insulin signalling and Klotho in longevity. Specifically we will identify the FOXO/DAF-16 target genes up- or down regulated in long-lived C. elegans mutants.

Self-funding applicants are welcome. In addition to tuition fees, bench fees of between £3-£15,000 per annum are required depending on the nature of the project.

Home/EU – for September- June 30th, for January-October 31st and Overseas for September- May 31st, for January- September 30th

• Dr Tarja Kinnunen

The project will explore the evolution and polymorphic variation of molybdoflavoenzymes, aldehyde oxidase and xanthine dehydrogenase involved in drug and xenobiotic metabolism in diverse species using genetically engineered cell lines / organisms, bioinformatics, structural biology and enzyme kinetics.

There is currently no funding for this project and we encourage interested self-funding students to apply. In addition to tuition fees, bench fees of £8,000 per annum are required.

Home/EU -June 30th/October 31st and Overseas May 31st/September 30th

• Dr Douglas Clarke

The project will explore the evolution and polymorphic variation of vitamin K epoxide reductases involved in coagulation, bone development and protection against oxidative stress in diverse species using genetically engineered cell lines and organisms, bioinformatics, structural biology and enzyme kinetics.

There is currently no funding for this project and we encourage interested self-funding students to apply. In addition to tuition fees, bench fees of £8,000 per annum are required.

Home/EU -June 30th/October 31st and Overseas May 31st/September 30th

• Dr Douglas Clarke

Alkaliphilic microorganisms occupy a unique environmental niche where the pH is often >pH 9.0. In order to survive and thrive in these environments these microorganisms have developed a range of unique biochemical processes. This project will isolate undescribed organisms from a range of alkaline environments and characterise biochemical and environmental capabilities of these organisms.

Self-funding applicants are welcome. In addition to tuition fees, bench fees of £xx per annum are required.

Home/EU -June 30th/October 31st and Overseas May 31st/September 30th

• Professor Paul Humphreys
• Professor Andrew Laws

Members of the Tumour Necrosis Factor Receptor (TNFR) family regulate epithelial cell growth / proliferation as well as cell death and autophagy pathways. Our previous work has demonstrated for the first time how members of the TNFR family, such as CD40, regulate growth versus apoptosis in normal, malignant and ‘para-malignant’ cells with defined genetic alternations. Understanding the precise mechanisms underlying the actions of these receptors will allow the design of novel, tumour-specific anticancer therapies.

Self-funding applicants are welcome. In addition to tuition fees, bench fees of £12,500 per annum are required.

Home/EU -June 30th/October 31st and Overseas May 31st/September 30th

• Dr Nikolaos Georgopoulos

Microbiology has an impact on a range of processes that impact the safe disposal of radioactive wastes. We have a long running interest in the degradation of cellulose based radioactive wastes at high pH and the fate of gases such as methane, hydrogen and carbon dioxide.

Self-funding applicants are welcome. In addition to tuition fees, bench fees of £5,000 per annum are required.

Home/EU -June 30th/October 31st and Overseas May 31st/September 30th

• Professor Paul Humphreys

The choanoflagellates are a group of unicellular eukaryotes known to be the closest relative of animals. Gene sequences from RNA-Seq transcriptome data are over-turning our views on how different groups of choanoflagellate species are related to each other. Through comparative genomics we can also gain a better understanding on the evolution of important traits such as multicellularity, protein translation, RNAi and virus-like genetic parasites. This project aims to generate robust and reliable evolutionary trees to test current ideas on choanoflagellate evolution. The use of reliable trees will allow a more accurate reconstruction of trait evolution in choanoflagellates and in the last common ancestor of choanoflagellates and animals.

Self-funding applicants are welcome. In addition to tuition fees, bench fees of between £3-£15,000 per annum are required depending on the nature of the project.

Our standard University deadlines apply. Please see our Deadlines for Applications page to find out more

• Dr Martin Carr

Rodents from the genus Apodemus are the most common mammals of the Paleoarctic region. They occupy environments as different as Spain and Siberia, contribute to spread of human diseases like Lyme disease and tick-borne encephalitis; some apparently separate species, A. flavicolis and A. sylvaticus, live in sympatry in the forests and fields of the European Plains. Apodemus are a rich target for evolutionary studies on hybridisation, host–pathogen interactions and adaptations. However, they are very underdeveloped in terms of their genomic and genetic resources. For example, most of the published work use short fragments of mtDNA and around 10 microsatellites to study phylogeogaphic relationships between populations of Apodemus in Europe and Asia. Thanks to several collaborations with researchers in UK and Europe, we have developed whole-genome sets of SNP markers to study Apodemus phylogeography and metabolic biology. We have also recently developed a RAD-seq pull-down protocol to facilitate extraction of a common set of loci from samples with degraded DNA.

In this project, we will use this newly developed protocol to access DNA from an extensive collection of local Apodemus samples from Białowieża forest in Poland, dating back to the second World War, to recover spatial and temporal patterns of genetic diversity of the Apodemus population across 50+ years of observations. This unique time-travel approach will provide an unprecedented insight into evolutionary forces shaping a wild rodent population in one of the last few primeval ecosystems in Europe.

Self-funding applicants are welcome. In addition to tuition fees, bench fees of between £3-£15,000 per annum are required depending on the nature of the project.

Our standard University deadlines apply. Please see our Deadlines for Applications page to find out more

• Dr Jarek Bryk

Using human disorders of keratinisation as a model, the role of keratinocyte adhesion for the function of the epidermis will be studied. Rare genetic skin diseases are pathophysiologically heterogeneous; disturbed cell adhesion based on faulty protease pathways is major mechanism of these disorders. We want to study these mechanisms to understand the importance of proteases and protease inhibitors in the etiology of skin diseases and reveal signalling pathways involved in these processes. Keratinocytes will be analysed in primary and organotypic cell culture and their alterations characterised in particular disorders.

Self-funding applicants are welcome. In addition to tuition fees, bench fees of £5000 per annum are required for the MSc by Research and £8000 per annum for the PhD

Home/EU – for September- June 30th, for January-October 31st and Overseas for September- May 31st, for January- September 30th

• Dr Hans Hennies

Outline The aim of the project is an efficient and targeted transport of functional proteins into the viable epidermis. Using the genetic skin disease congenital ichthyosis as an example, the applicability of specific gene expression systems will be studied. Congenital ichthyosis can be caused by deficiency of a range of enzymes, including transglutaminase 1 and epidermal lipoxygenases, which are involved in the final steps of lipid metabolism and keratinocyte differentiation in the skin. The efficacy of treatments with recombinant enzyme produced in different species, such as E. coli, insect or mammalian cells, will be assessed. Assays for the analysis of enzyme activity have to be developed. In vitro disease models have to be established using 3D full-skin models, and cell lines, primary keratinocytes and skin models will be treated and characterised regarding protein uptake and activity, subcellular localisation, biological availability, and adverse effects.

Self-funding applicants are welcome. In addition to tuition fees, bench fees of £9,000 per annum are required for this project.

Home/EU – for September- June 30th, for January-October 31st and Overseas for September- May 31st, for January- September 30th

• Dr Hans Hennies

The molecular control of skin development and the switch from cell proliferation to differentiation are not well understood. A key regulator in this process is the transcription factor p63. We want to study the expression of TP63 in differentiating human epidermal keratinocytes and identify the role of different isoforms over time. We will then focus on the isoform TAp63 and terminal differentiation because disturbed epidermal barrier function is involved in several diseases including rare skin diseases such as congenital ichthyoses and common complex diseases such as atopic dermatitis. We will use RNA-seq and qRT-PCR to identify differential gene expression and generate various cell models with transient and permanent gene knockdown. Full-skin models will be generated to study changes in epidermal morphology, gene expression, cell adhesion, and skin barrier function. Genome editing with CRISPR/Cas9 will be used to obtain knockout cells and specific mutants. Results will describe a regulatory network that is critical for skin development and homeostasis.

Self-funding applicants are welcome. In addition to tuition fees, bench fees of between £3-£15,000 per annum are required depending on the nature of the project.

Home/EU – for September- June 30th, for January-October 31st and Overseas for September- May 31st, for January- September 30th

• Dr Hans Hennies

Lyme disease and Relapsing Fever are vector-borne diseases resulting from infection by bacteria of the Borrelia genus. Borrelia burgdorferi, an obligate parasite, has evolved complex immune-evasion strategies to survive extended periods of time in the mammalian host. The aim of this project is to improve our understanding of this unusual pathogen by studying a range of bacterial surface proteins and how they interact with a range of molecules in human blood.

Self-funding applicants are welcome. In addition to tuition fees, bench fees of £6,000 per annum are required.

Home/EU -June 30th/October 31st and Overseas May 31st/September 30th

• Dr Richard Bingham
• Dr Christopher Cooper

Impairment of the epidermal barrier function is a pathophysiological feature of several genetic skin diseases. Recent work has demonstrated that the barrier is compromised because of lack of long chain ceramides in cases of congenital ichthyosis. Here we want to study therapies for patients with a deficiency of ceramide synthase 3 which is located in the membrane of epidermal keratinocytes. Genome editing with CRISPR/Cas9 will be used to modify and correct CERS3, the gene for human ceramide synthase 3. The subcellular localisation of the enzyme will be assessed and the function is studied by characterising functional domains and enzyme activity, its activation and downregulation and potential binding partners. Using 3D full-skin models in vitro. The role of ceramide synthase activity in normal and pathological epidermal differentiation will be determined with a focus on the permeability barrier function and its restoration.

Self-funding applicants are welcome. In addition to tuition fees, bench fees of £9,000 per annum are required for this project.

Home/EU – for September- June 30th, for January-October 31st and Overseas for September- May 31st, for January- September 30th

• Dr Hans Hennies

It is well established that aging is a progressive deterioration of an organism’s cellular structures and homeostatic mechanisms, with an increasing decline with age in an organism’s ability to correctly perform normal cellular functions. Mitochondrial DNA (mtDNA) damage arising from respiration-associated reactive oxygen species or inaccurate mtDNA replication and repair is linked with normal and premature aging, and other age-associated degenerative disorders affecting healthspan.

Little is known of how mitochondria repair the damage to their DNA, and in particular, the roles of lesion bypassing DNA polymerases, several of which may be targeted to the mitochondria. Some DNA polymerases may exhibit either protective or mutagenic effects on mtDNA, suggesting their deregulation could influence not only cancer development, but mitochondrial aging and hence normal life- and healthspan.

We will study these DNA polymerases to assess how they influence mtDNA integrity in human cells using in vivo and in vitro approaches, and also if they influence organismal lifespan with the Caenorhabditis elegans worm model system. The project brings together UK and international laboratories in the fields of genome integrity, metabolism, C. elegans and oxidative DNA repair.

Self-funding applicants are welcome. In addition to tuition fees, bench fees of between £3-£15,000 per annum are required depending on the nature of the project.

Home/EU – for September- June 30th, for January-October 31st and Overseas for September- May 31st, for January- September 30th

• Dr Christopher Cooper

The normal function of the epithelial cells that line the intestinal mucosa is dependent on their close interaction with the vast and complex micro-flora that resides in the intestine. Most in vitro research in this area has concentrated on the effects of individual bacterial species grown as platonic cultures. This project will investigate the role of biofilms which is more representative of conditions found in the native intestine.

Self-funding applicants are welcome. In addition to tuition fees, bench fees of £15.000 per annum are required.

Home/EU -June 30th/October 31st and Overseas May 31st/September 30th

• Dr Andrew Collett

Outer membrane vesicles which are actively secreted from the outer membrane of Gram negative bacteria could have an important role in mediating the host’s response to a range of bacteria. This project will use a variety of in vitro cell models to help understand the cellular processes which drive these potentially pathogenic responses.

Self-funding applicants are welcome. In addition to tuition fees, bench fees of £15,000 per annum are required.

Home/EU -June 30th/October 31st and Overseas May 31st/September 30th

• Dr Andrew Collett

The principle substrate for energy transfer in mammalian cells is ATP, although other nucleotide phosphates play vital roles in specific processes. Some bacteria are capable of using alternative sources of energy such as long chain polyphosphates, and some can use both ATP and polyphosphate as phosphoryl-donors. Certain mammalian cell types contain significant amounts of polyphosphate concentrated in to specific organelles but its role or purpose in these sites is not known. The proposed PhD project is aimed at investigation of these polyphosphates to attempt to establish whether they have a metabolic function or activity, how they are synthesized and how they are bound in particular organelles. The project will use a variety of cell biological and molecular techniques as required, including high resolution NMR to study the metabolism of known polyphosphate substrates.

Self-funding applicants are welcome. In addition to tuition fees, bench fees of £6,000 per annum are required.

Home/EU -June 30th/October 31st and Overseas May 31st/September 30th

• Dr Shamus Burns

The aim of the project is an efficient and targeted transport of functional proteins into the viable epidermis using innovative drug delivery systems. Using congenital ichthyosis as an example, options for topical treatment of skin diseases will be studied. Suitable cellular model systems including reconstituted skin have to be developed. Skin models will be assessed for the therapeutic outcome by analysing protein uptake, cell interactions, cellular localisation, biological availability, and the fate of the substituted protein in differentiating keratinocytes and skin.

Self-funding applicants are welcome. In addition to tuition fees, bench fees of between £3-£15,000 per annum are required depending on the nature of the project.

Home/EU – for September- June 30th, for January-October 31st and Overseas for September- May 31st, for January- September 30th

• Dr Hans Hennies

We have previously shown how specific genetic alterations implicated in cancer (over-expression of human telomerase, inactivation of p53 and p16 tumour suppressors, constitutive activation of receptor tyrosine kinases, RTKs, abrogation of cell adhesion by functional inactivation of E-cadherin) alter epithelial cell life-span, growth, cell:cell adhesion and responses to death signals. Unravelling the influence of these changes in epithelial cell behaviour at the molecular level, and studying the role of cancer-driving signalling pathways such as those triggered by RTKs, Wnt/beta-catenin and p63 family proteins, will a) help us improve our understanding of the process of carcinogenesis, b) allow better disease prognosis and c) permit the design of tailored, patient-specific therapies.

Prospective students who have secured government sponsorships/scholarships are welcome to apply as are self-funded applicants. In addition to tuition fees, bench fees of £12,500 per annum are required.

Home/EU -June 30th/October 31st and Overseas May 31st/September 30th

• Dr Nikolaos Georgopoulos

A main theme of our research is to understand the precise cell signalling mechanisms that dictate epithelial cell behaviour and fate, ranging from cell proliferation / growth, molecular and functional specialisation (cytodifferentiation), to induction of cell death (e.g. apoptosis). Our aim is to understand how these processes are inappropriately regulated in pathological conditions / disease. More specifically, our skin-related research involves using physiologically relevant biological models to explore, at the cellular and molecular level, the underlying mechanisms of a) defective wound healing and b) chemotherapy-induced alopecia. This will permit the improvement of existing medical devices to a) improve wound healing in the clinic, and b) reduce chemotherapy induced hair loss, one of the most distressing side effects of cancer chemotherapy), as well as the design of novel technologies with the aim to provide improved relevant therapeutic intervention strategies. For these projects we have major industrial collaborations with a) VeritaCell (http://veritacell.com/) and b) Paxman (http://paxman-coolers.com).

Prospective students who have secured government sponsorships/scholarships are welcome to apply as are self-funding applicants. In addition to tuition fees, bench fees of £12,500 per annum are required.

Home/EU -June 30th/October 31st and Overseas May 31st/September 30th

• Dr Nikolaos Georgopoulos