The JBU’s staff and students focus on research projects across a wide range of topics associated with bladder function and disease. Work in the lab spans areas of fundamental research to clinical and applied projects.
Jenny Southgate began her career at the Imperial Cancer Research Fund (ICRF) in London, where she obtained a degree from the Institute of Biology, followed by a PhD from the University of Leeds. She moved to Leeds in 1990, where she headed a research group based in the ICRF Cancer Medicine Research Unit at St James's University Hospital, University of Leeds.
She took up the post of Director of the Jack Birch Unit in October 1999. This post is sponsored by a programme grant from York Against Cancer.
Jenny’s research interests encompass the cell/molecular biology of human epithelial tissues and their cancers, primarily focusing on the urothelium of the urinary bladder. Her strategy has been to develop cell and tissue culture systems for normal human urothelial (NHU) cells which can be used to examine the pathways that regulate tissue homeostasis. The research has led to approaches that enable NHU cells to be propagated in vitro and manipulated to form functional differentiated tissues. This is used as a platform for gaining insight into bladder diseases including interstitial cystitis and cancer. A potential application of the research being explored is the use of regenerative medicine approaches (tissue engineering stem cells and biomaterials) to restore bladder function following trauma or diseases, such as cancer.
Simon Baker did both his graduate BSc degree and PhD at the University of York. He has previously held Yorkshire Enterprise, Royal Society of Edinburgh/BBSRC Enterprise and Wellcome Trust VIP Fellowships.
In 2010, Simon and Prof Southgate won the $300,000 Astellas European Foundation Urology Prize which is being used to examine the gene expression of human bladder epithelium (“urothelium”). We are studying the genes which give human urothelium its unique properties such as the urinary barrier, remarkable wound healing and detoxifying enzymes. Our approach is to start from an understanding of how the normal (non-cancerous) tissue functions and then evaluate how features of the tissue’s specific biology might be hijacked by cancers to support their unregulated growth.
For example, some cancers retain features that are associated with the normal tissue and these retained features can give us clues to how the tumour functions. If a particular cancer has retained a feature of the normal tissue, it is likely that this is in some way associated with tumour survival and growth.
Simon is interested in the adaptive responses of the bladder epithelium (“urothelium”) to urinary toxins. Human urothelium forms a barrier to prevent exposure of the cells to urine. Sometimes (such as in disease) the barrier can fail or be damaged and Simon is working on evidence that the cells can metabolise/break-down some urinary toxins allowing them to survive exposure and the tissue to repair.
The urothelium spends your whole life exposed to concentrated toxins in the urine. Some of these toxins damage the DNA and we are looking at whether certain chemicals leave their signature on the DNA in the form of specific mutation types. These “mutational signatures” might help explain the cause of the cancer in each individual and help guide treatment approaches.
Andrew has a BSc (Honours) in Evolutionary Biology from the University of Edinburgh and recently completed a BBSRC CASE PhD Studentship at the Roslin Institute in Animal Disease and Genetic Resistance. Moving away from avian genomics, Andrew joined the Jack Birch Unit as a postdoctoral associate in November 2017 to apply his skills in bioinformatics to various human bladder disease projects.
With the sheer volume of ‘omics’ data available to researchers, there is great potential for the elucidation of many poorly understood human diseases. However, such data need to be analysed and interpreted carefully, always coming back to the true biology rather than focusing purely on statistical significance. Andrew’s interest is the study of modulated expression patterns and how these are driven, whether through changes in regulatory elements, coding mutations or genomic structural variants. In the JBU, Andrew works on bladder cancer, interstitial cystitis and identifying expression signatures in established bladder epithelial models.
Sreemoti completed her MSc in Molecular Genetics at the University of Leicester and was appointed as a Research Assistant at the University of Oxford. She then pursued her PhD degree at the Hull York Medical School, University of Hull and was then appointed as a Postdoctoral Research Associate at the University of Manchester. She next joined the Jack Birch Unit as a Postdoctoral Research Associate on a BBSRC-funded project that aims to characterise the transcriptome and epigenome of the urothelial cells.
Despite being a mitotically quiescent tissue, the urothelium displays remarkable regeneration potential in the event of injury. Without any strong evidence for the existence of urothelial stem cells, it is being hypothesised that the urothelial cells possess inherent plasticity that allow them to adapt to changes in their local niche. Sreemoti is interested in isolating the different cell types of the urothelium and defining their transcriptomic and epigenomic signatures. Her project will further investigate whether altering the transcription and epigenetic machinery influences the differentiation and regenerative potential of the urothelium. This project aims to develop an insight into the adaptability of the urothelium to contextual and epigenetic alterations which will be crucial in the development of targeted regenerative therapies to treat urothelial disorders.
Jenny joined the group in January 2004 after obtaining a BSc in Cell Biology from Durham University and completed her PhD in 2016 whilst working part-time in the Jack Birch Unit. Jenny is primarily responsible for managing the histology, microscopy and immunochemistry facilities for the Jack Birch Unit, as well as providing research & training support for the group.
Jenny’s main research interest is in understanding the role of gap junctions in intercellular communication in regulating homeostasis and repair of normal and diseased or malignant urothelium.
Ros graduated from Liverpool University in 1993 with a BSc in Freshwater Biology. She started work at the University of York in 1998 working in the Medical Cryobiology Unit to research methods for cryopreservation of single cells and tissues. She joined the Jack Birch Unit in 2003.
Ros’ main role is the management of the unit’s tissue culture facility. This involves overseeing the smooth running of the tissue culture laboratory, providing training to staff, students and visitors. She also takes charge of isolating primary cells from tissue samples to establish urothelial cell lines and is involved in a number of research projects.
Jo graduated from the University of York in 2002 with a BSc and MSc in Molecular Biology, followed by a PhD from the University of Manchester in 2006. She then returned to York and after completing a BBSRC funded Post Doc in the YCR Cancer Research Unit, took a career break in 2010 to look after her family. She then joined the Jack Birch Unit in 2011 as a research technician.
Jo provides molecular biology support to all members of the group.
Claire graduated from Liverpool John Moores University with a BSc in Applied Biochemistry, followed by a PhD from the University of Sheffield. After completing a BBSRC-funded Postdoctoral research position in Manchester, Claire joined the Jack Birch Unit in 2000 on a Wellcome Trust-funded Postdoctoral position. She had a career break in 2013 and recently returned to the Jack Birch Unit as a Research Technician. Claire has experience in a wide range of cell biology and molecular biology techniques and offers support in these areas.
Claire is interested in mechanisms of urothelial differentiation and how this is affected in disease conditions including cancer, interstitial cystitis and urinary tract infection.
Claire established a method for differentiating normal human urothelial (NHU) cells. She discovered that differentiation is induced in NHU cells following activation of the nuclear receptor, PPARγ, which itself required inhibition of EGF receptor signalling. The gene expression programme induced during urothelial differentiation includes the uroplakins (UPK1a, UPK2, UPK3a), cytokeratins (CK20, CK13) and tight junction proteins (ZO1, ZO3, claudin 3), whilst CK14, a marker of squamous metaplasia is down-regulated. The PPARγ-induced differentiation acts indirectly on these differentiation genes via transactivation of a network of transcription factors, including FOXA1 and IRF-1. A subset of patients with interstitial cystitis were found to have urothelium with compromised potential to differentiate via the above PPARγ-induced mechanism.
Debora Morgante is a Paediatric Surgeon based in Yorkshire. She obtained her Master’s degree in Medicine and Surgery at ‘Sapienza’ University of Rome (Italy), with the published experimental thesis ‘Vesico-Ureteral Reflux and Renal Function in Patients with Posterior Urethral Valves: a Thirty-Year Analysis’ (Urology, 2011). Subsequently Debora specialised cum laude in Paediatric Surgery with the experimental thesis ‘Paediatric Robotic Pyeloplasty: Learning Curve and Preliminary Outcome’, under the supervision of Prof Denis A. Cozzi (Paediatric Surgery - ‘Sapienza’ University of Rome/Policlinico ‘Umberto I’) and Prof Ramnath Subramaniam (Paediatric Urology – Leeds General Infirmary).
Debora is currently working in the JBU as a Clinical Research Fellow and is registered for a PhD through HYMS. She is supported on a grant from the Medical Technologies Innovation and Knowledge Centre and is supervised by Professor Jenny Southgate and Mr Ramnath Subramaniam (Consultant Paediatric Urologist at Leeds General Infirmary).
Debora is passionate about Paediatric Surgery (with particular interest in Neonatal Surgery and Paediatric Urology) and Basic Science Research (with particular interest in Biomaterials, Tissue Engineering and Regenerative Medicine).
A number of congenital and acquired diseases of the urinary bladder culminate in end-stage disease characterised by small contracted bladders that are susceptible to recurrent infections and create high pressure systems that can cause irreversible damage to the kidneys. Reconstructive surgery in end-stage bladder disease aims to reduce pressures in order to prevent kidney damage. A treatment option is to incise the scar tissue and detrusor muscle of the damaged bladder wall in order to make the inner lining of the bladder (mucosa) bulge. This procedure is known as auto-augmentation or detrusorotomy and can increase bladder capacity and reduce bladder pressures. Because of a high risk of bladder perforation from the procedure, there have been some attempts to cover the bulge with flaps from a variety of vascularised tissues. Debora is testing the possibility of using a novel biomaterial called PABM (porcine acellular bladder matrix), developed previously by the JBU as a tissue-integrative support material for urinary bladder auto-augmentation.
Tom obtained a BSc (Honours) in Medical Genetics from Swansea University before graduating from the University of Liverpool with an MRes in Biomedical Sciences & Translational Medicine. He is currently studying for a PhD funded by York Against Cancer and is supervised by Professor Jenny Southgate and Dr Simon Baker.
The lack of progress made in generating viable treatments for muscle-invasive bladder cancer over the past two decades highlights the pressing need to devise novel, targeted therapies for the disease. Work undertaken in the lab using Normal Human Urothelial (NHU) cells in vitro has found that these cells in a proliferative state activate different growth-regulating signal transduction pathways to NHU cells that have undergone differentiation.
Tom’s project will utilise a mix of bladder cancer cell lines alongside the established NHU system to explore what pathways drive urothelial tumorigenesis and growth in basal-like urothelial cancers compared to cancers with a more differentiated, ‘luminal’, phenotype. Knowledge of alternative signalling pathways that power the different subtypes of bladder cancer will stratify muscle-invasive bladder cancer and identify potential therapeutic targets.
Zhen Liu has a BSc in Drug synthesis and design from Tianjin University of Science & Technology and an MSc in Biotechnology from New York University before working as a research assistant in SIBET of Chinese Academy of Sciences. He is currently studying for a PhD supervised by Professor Jenny Southgate and Dr Dawn Coverley.
Although some of molecular changes that accompany the activation of the specific nuclear receptor PPARγ during urothelial differentiation are understood, there is much still unknown. It is becoming evident that in addition to changes in chromatin organisation that influence gene expression, there are accompanying alterations to the nuclear architecture upon which the DNA and accompanying machinery is scaffolded to establish specific gene expression programmes. Zhen Liu’s project will use in vitro approaches to illustrate the role and compartmentalisation of PPARγ isoform 1 and PPARγ isoform 2 in urothelial cytodifferentiation as well as neoplastic transformation events.