Fixed-term

Angiogenesis is a biological process by which new capillaries are formed from pre-existing vessels. It is well established that brain tumour growth depends on angiogenesis. Anti-angiogenic therapies directed against the tumour vasculature should deprive the tumour of oxygen and nutrients and therefore represent a powerful adjuvant to traditional therapy. Therapeutic approaches aimed to avoid the binding of pro-angiogenic factor VEGF to its receptor have therefore attracted considerable attention. However, although current anti-VEGF therapies lead to an initial reduction in the size of the tumour, this progression free period is transient and inevitably followed by a second phase of massive regrowth. Recent findings indicate that anti-VEGF evasion is associated to revascularisation of the tumour and to a strong increase in the invasiveness of the tumoral cells, but the molecules implicated in this process are not known yet. This project aims to identify molecular targets implicated in anti-VEGF evasion in glioblastoma patients. The PhD project will involve in vitro culture of glioblastoma cells derived from patients. These cultures will be characterised using molecular and cellular biology techniques including qPCR, western blot and immunofluorescence confocal microscopy. The response of patient-derived cells to anti-VEGF treatments will be analysed using cutting-edge -omics approaches, such as RNA-seq and proteomics. The successful candidate will be extensively trained in these techniques as well as in improving presentation skills by participating in weekly laboratory meetings, internal student seminar series and presenting data in relevant conferences in the field.  For further information regarding the project or an informal discussion please contact Director of Studies, Prof Angel Armesilla   a.armesilla@wlv.ac.uk

In recent years our understanding of the molecular basis of cancer development and evolution has improved greatly. However, there is still much to be discovered about the molecular biology that determines the spread (metastasis) of tumours to distant organs. Breast cancers often metastasise to the brain and the prognosis for patients with breast-to-brain metastasis is very poor. There is relatively little known about which genes, and associated molecular pathways, are disrupted in cells that have the potential to metastases to, and then proliferate in, the brain. We have been investigating the molecular basis of breast-to-brain metastasis for several years and recently carried out an exome sequencing screen to identify genes that are commonly mutated in these tumours. We believe that the gene mutations this screen identified may contribute to several processes involved in metastasis to, and eventual proliferation within, the brain. This PhD project will investigate the role of these genes (their encoded proteins) in metastasis and investigate how loss of function mutations in these genes change cellular pathways/networks that regulate metastatic progression.  The aim of this work is to identify prognostic markers for, and therapeutic targets against, breast tumours that may metastasise to the brain which will ultimately result in clinical benefit. Techniques The PhD student will gain experience in state-of-the-art biomedical research methods and techniques including gene editing, next generation sequencing techniques such as RNAseq, bioinformatic analysis, cell culture and tumour modelling, tumorigenicity assays, immunofluorescence, confocal microscopy, western blotting, flow cytometry, quantitative PCR and associated cell biology techniques. For further information regarding the project or an informal discussion please contact Director of Studies, Dr Mark Morris  m.r.morris2@wlv.ac.uk

Supervisory Team: Professor Weiguang Wang, Professor Basu Supratik, Dr Vinodh Kannappan Background: Multiple myeloma (MM) is the second most common blood cancer. Current best therapeutic options involve combining a proteasome inhibitor with one of the immunomodulatory imide drugs (IMiDs, lenalidamide or pomalidomide). All MM patients are ultimately relapsed. MM contains cancer stem cells (CSCs) commonly located in poorly vascularised regions. CSCs are typically associated with resistance to chemotherapy. Therefore, development of new drugs with immunomodulatory and CSC-targeting effect is of clinical urgency. Disulfiram (DS), an anti-alcoholism drug, demonstrates excellent activity against a wide range of cancers without toxicity to normal cells. DS chelates copper and zinc to form copper-diethyldithiocarbamate (Cu-DDC) and zinc-diethyldithiocarbamate (Zn-DDC) which are the active anticancer compounds. The anticancer activity of DS, Cu-DDC and Zn-DDC has been known for more than three decades. Its application in cancer clinic is limited by the very short half-life of these compounds in the bloodstream (< 4 min) and insolubility. Our team developed nanoparticles encapsulated DS, Cu-DDC and Zn-DDC which are injectable with long half-life (7 hours) showing strong anticancer efficacy in numerous cancer animal models. In our pilot studies, PEGylated liposome encapsulated Zn-DDC had stronger immunomodulatory and anti-MM effect than currently available IMiDs. It also reverses CSC-induced resistance and synergistically enhances the anti-MM activity of IMiDs. Methodologies: 1. Using high-pressure homogenizer to generate PEG-Lipo/Zn-DDC and Cu-DDC. 2. Using MTT cytotoxicity to test the anti-MM activity. 3. Investigating the effect of PEG-Lipo/Zn-DDC and Cu-DDC on IKZF1/3-IRF4-cMYC-IL2 immunomodulatory pathway. 4. Examining the effect on CSCs. Outcomes: 1. Development of PEG-Lipo/Zn-DDC and Cu-DDC; 2. Examination of the anti-MM effect of PEG-Lipo/Zn-DDC and Cu-DDC; 3. Elucidation of anti-MM mechanisms.

Background: Crohn’s disease (CD) is a chronic relapsing incurable inflammatory bowel disease (IBD) affecting approximately 165/100000 people in the UK. The cytokine milieu in the intestine is an important factor in the maintenance of the immune balance, and in gut inflammation, this balance is dysregulated resulting in mucosal inflammation.  The gastrointestinal tract interacts with a huge variety of diverse microbiota. Changes in the diversity of this microbiota (dysbiosis) is associated with changes in the cytokine profile and considered to be an important factor in the aetiology of CD. Monoclonal antibody therapy has revolutionised the treatment of IBD. However, many patients do not respond to the drugs and some develop serious side effects and/or recurrence after the treatment is discontinued. Furthermore, information on the effect of biological drugs on the bacterial composition in relation to the systemic cytokine profile in CD is still unknown. Hypothesis: Dysbiosis in CD correlates with systemic changes in the production of pro- and anti-inflammatory cytokine. Aims: To characterise dysbiosis in CD and examine concurrent changes in gut bacteria and serum cytokine profiles in response to treatment with biological drugs including vedolizumab and infliximab. Research Plan: Pro- and anti-inflammatory cytokines, immune cell phenotype and activation will be assessed by flow cytometry on serum and blood immune cell samples obtained from CD patients.  Bacterial DNA will be extracted from stool samples and dysbiosis of gut microbiota will be assessed before and after biological treatment using Luminex technology and GA-map Dysbiosis Test.  Advanced statistics and bioinformatics will be used to determine the relation between the cytokine levels and dysbiosis. Outcome: The data obtained will potentially help predict patient response to biological drugs and will bring closer the notion of personalised medicine. For further information regarding the project or an informal discussion please contact Director of Studies, Dr Hafid Omar  h.omar6@wlv.ac.uk

Approaches for culturing mammalian cells in vitro are increasingly needed to study cell and tissue physiology and to grow replacement tissue for regenerative medicine. For this purpose, a scaffold that incorporates sophisticated biochemical and mechanical cues, mimics the extracellular matrix found in vivo and supports the growth of tissue in three-dimensional (3D) is required. An ideal scaffold should fulfil several criteria including biocompatibility, biodegradability into non-toxic components that are easily excreted by the host, possess an interconnected network of pores of a diameter that permits cell migration and surface chemistry that encourages cell attachment and permits the immobilisation of biomolecules such as growth factors. Biomaterials (hydrogels and porous polymer materials) that can serve as scaffolds for 3D cell culture and tissue engineering are developed in Dr Eissa’s group using modern synthetic chemistry and bioconjugation methodologies. Recent work has shown that these scaffolds are capable of supporting 3D growth of many cell types including human pluripotent stem cells, human haematopoietic stem cells and human endometrial cells. This interdisciplinary project will involve creating a range of complex architecture materials that can serve as scaffolds for the culture of cells and, ultimately, tissue in 3D. This will entail the utilisation of the state-of-the-art methodologies including emulsion templating and additive manufacturing 3D printing technologies. One produced, accurately optimised and validated, scaffolds will be used to establish optimal in vitro tissue model to solve a biomedical problem in mind. The outcome will be a robust platform for investigating cell physiology and fabricating tissue in vitro. This will have significant implications which will increase the efficiency of the discovery process and translation of biomedical materials and deliver a ‘step change’ in understanding the cause of diseases and accelerating therapies development. Experience in subject areas such as Chemistry, Biochemistry, Biomedical Science, Bioengineering or a related field is required. Much of the work will involve working at the interface between materials chemistry and biology. Prior experience is desirable but appropriate training in a range of chemical and biomedical techniques will be provided to the successful candidate. Laboratory work will be undertaken within the University of Wolverhampton’s Life Sciences Centre, the Rosalind Franklin building, which houses a broad range of state-of-the-art research facilities suitable for undertaking this multidisciplinary project. Nevertheless, the work will involve collaborations with external research groups in the UK and beyond (Europe and Australia), providing great experience for the successful candidate. Applications are welcomed from students with all backgrounds that are suitably qualified and highly motivated. Further details (or informal enquiries) can be obtained via direct email to Director of Studies, Dr Ahmed Eissa A.M.Eissa@wlv.ac.uk