Biological Sciences (PhD)

Vitamin K is associated with cancer incidence and mortality suggesting that vitamin K dependent (VKD) post-translational gamma-carboxylation of proteins are involved in pathological outcomes. This project will identify post-translational gamma-carboxylation of proteins in normal and cancer cells using immunochemical and mass spectrometry analysis to understand vitamin Ks role in cancer.

Self-funding applicants are welcome. In addition to tuition fees, bench fees of £6000 per annum are required for this project.

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

• Dr Douglas Clarke

In recent years, several studies of human skin diseases have used 3D cellular skin models consisting of a dermal equivalent containing fibroblasts and an epidermal equivalent made with keratinocytes. These models replicate the layered structure of the skin and they can be used to mimic various skin diseases characterised by compromised epidermal barrier function. Currently, production and characterisation of such models relies on the use of media and other reagents based on animal resources. Here we want to replace these compounds with animal-free reagents and establish a pipeline for the analysis of skin models without using animal products. The production of cellular models is limited by the supply of primary human fibroblasts and keratinocytes. In a second step, we will produce skin models using keratinocytes derived from human induced pluripotent stem cells (iPSCs). The iPSCs are generated from primary fibroblasts isolated from human tissue samples, i.e., they are specific for the proband and represent exactly their genetic background. Full-skin models will then be used to study gene expression and epidermal barrier function in health and disease.

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

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

• Dr Hans Hennies

Cannabinoids have an established role in the exertion of palliative effects in cancer patients. They have been used in cancer patients to relieve nausea, vomiting, pain, and to help stimulate appetite. Standard treatment strategies for cancer patients may involve surgery followed by chemotherapy and radiation therapy. Unfortunately, patients experience many adverse effects associated with chemotherapy and radiation therapy. Some patients also show resistance to the treatments. Therefore, novel treatment methods are unmet clinical needs. We and others have shown that cannabinoids can also induce cytotoxicity in various cancers such as gynaecological and gastrointestinal cancers. The aim of the project is to continue the investigation and test non-psychoactive cannabinoids such as CBD (cannabidiol) and CBG (cannabigerol) on human carcinoma cells. In our projects, we are interested in investigating the mechanism of action of cannabinoids to induce cytotoxicity in tumours and whether treatment with cannabinoids can increase the sensitivity of cancer cells to chemotherapy and radiation therapy. The results of the pre-clinical project will inform clinical colleagues in designing clinical trials. Our ultimate aim will be: (1) whether cannabinoids can be used as adjunct treatment with the current treatment regimens for cancer patients to reduce the side effects associated with chemotherapy and radiotherapy, (2) whether the life expectancy of cancer patients can be increased if cannabinoids are added to the treatment strategy, (3) whether patients’ quality of life can be improved.

Self-funding applicants are welcome. In addition to tuition fees, bench fees of between £7-£10,000 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 Farideh Javid

Cell migration and invasion are drivers of tumour dissemination in high grade tumours such as Glioblastoma (GBM). Recurrence of tumours after initial treatment is the cause of death in brain tumour patients. Our research focus has been on the prevention of cancer cell dissemination and therefore improving survival by targeting cell migration using a panel of migrastatic inhibitors. Our results have indicated that there are specific migratory signatures in GBM cells which need to be considered when designing or developing anti-migratory drugs. This study will investigate the migratory signatures of the three subtypes in adult GBM, pro-neural, mesenchymal and classical, with the use of a panel of characterised migrastatic drugs. We will profile cell lines using Western blotting, immunofluorescence, gene silencing, immunohistochemistry in where applicable 2D and 3D migration and invasion models. The establishment of distinct migratory signatures will allow to pre-select patients for combination treatments with migrastatic drugs based on their migratory profile for enhanced drug activity in these patients.

Self-funding applicants are welcome. In addition to tuition fees, bench fees of £10,000 per annum are required for the project.

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

• Dr Anke Bruning-richardson

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 between £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

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 £8000 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

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

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

High grade brain tumours or glioblastomas (GBM) rank amongst the most aggressive tumour types due to their heterogeneity, diffuse and infiltrative nature and low survival. Recurrence of these tumours after initial treatment ultimately leads to the death of patients. One characteristic of GBM is the presence of hypoxic and necrotic regions. It is now believed that hypoxia and necrosis in these tumours drive the dissemination of tumour cells into healthy tissue within the brain and allows reseeding of a new tumour. We will investigate the role of Hif1alpha in this process in view of drug development to target hypoxia-associated pathways. We have recently identified members of the ARHGAP gene family to be involved in cell migration and invasion with some of these upregulated in hypoxic conditions and under the regulatory control of Hif1alpha. We will utilise patient derived cell lines representing the three different subtypes of GBM for 2D and 3D in vitro studies to expose to a panel of inhibitors under normoxic and hypoxic conditions. We will use tissue culturing, Western blotting, immunofluorescence microscopy, and gene silencing to assess the effect of targeting Hif1alpha and downstream effectors on cell migration/invasion and dissemination of tumour cells. The outcome of this project will be a characterisation of regulatory events involved in tumour dissemination as a result of hypoxia for targeted treatment in this cancer type.

Self-funding applicants are welcome. In addition to tuition fees, bench fees £10,000 per annum are required for this project.

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

• Dr Anke Bruning-richardson
• Professor Roger Phillips

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

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

The focus of this PhD is the pre-clinical screening and evaluation of different classes of novel compounds for potential anti-cancer activity. These compounds are available to test as part of a number of continuing and new collaborations with international chemistry research groups (in the UK and overseas). Key objectives are:- 1) phenotypic screening for toxicity against a range of cancer cell lines 2) analysis of selectivity towards cancer cells versus non-cancer cells and selection of lead compounds for further investigation. 3) analysis of activity against hypoxic cancer cells and other typically resistant cancer cells that are priority targets. 3) mechanism of action studies and target deconvolution of lead compounds.

Please see our Scholarships page to find out about funding or studentship options available.

• Dr Simon Allison
• Professor Roger Phillips

This MSc by Research is focused on the phenotypic approach to anti-cancer drug discovery. Key objectives are:- 1) phenotypic screening of novel compounds for activity against cancer cells, 2) analysis of selectivity towards cancer cells versus non-cancer cells, 3) analysis of activity against hypoxic cancer cells that are typically chemoresistant and a priority clinical target, 4) mechanism of action and target deconvolution studies. Depending on progress and interests, there is also the possibility of in ovo studies of ‘leads’ for ‘proof of concept’ in vivo evaluation.

Self-funding applicants are welcome. In addition to tuition fees, bench fees of £5000 per annum are required for this project.

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

• Dr Simon Allison

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 £10,000 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

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

The focus of this PhD is on the metabolic re-wiring of cancer cells which is now recognised as one of the hallmarks of cancer and is a potential rich source of new therapeutic targets. Specific aims are:- 1) to investigate cancer cell response to targeting specific molecular targets associated with metabolic re-wiring 2) to investigate heterogeneity in cellular response and potential biomarkers of response 3) to perform metabolic profiling of cancer and non-cancer cells and analyse how they respond to specific molecular targeting to provide insight into metabolic adaptability and dependency.

The project is for self-funding students from home or overseas. 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 Simon Allison
• Professor Roger Phillips

Cannabinoids can modulate the development of epidermal cells and are potential drugs for a range of skin diseases. Their activity depends on their interaction with certain cannabinoid receptors of keratinocytes, the molecules involved in these mechanisms are not well studied though. Keratinocytes have a clearly defined spatio-temporal differentiation pattern, which is represented by corresponding gene expression profiles. We want to study this interaction in a collaborative project by investigating effects of various cannabinoids on the development of the epidermis and the role of known cannabinoid receptors. Keratinocytes will be analysed in primary and organotypic cell culture and changes in their proliferation, differentiation, expression profiles and active pathways will be characterised. These studies have an impact on the prospective use of cannabinoids in therapies for inflammatory and other complex disorders.

Self-funding applicants are welcome. In addition to tuition fees, bench fees of £10,500 per annum are required.

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

• Dr Hans Hennies
• Dr Farideh Javid

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