PhD Studentship: Environmental factors including Cholestasis, Cytokines, and Stromal cell activati
To understand the molecular mechanisms that allows the extracellular environment to influence the expression of the Proline Rich Homeodomain (PRH) transcription factor and its downstream targets in bile duct epithelial cells to promote bile duct disease.
The Proline Rich Homeodomain (PRH/HHEX) protein is an oligomeric transcription factor with a role in tumour formation in a variety of cancers. PRH is required for liver and bile duct development and PRH expression is regulated by bile acids and can itself regulate transporter proteins found in the liver. Loss of PRH in hepatic precursors results in polycystic bile ducts and elevated collagen deposition indicating the importance of PRH in regulating bile duct formation.
Bile duct diseases including cholangitis, fibrosis and cancer are examples of complex diseases that involve a combination of genetic and environmental factors. Bile duct wounding, by exposure to toxins, metabolites (high bile acids/oxysterols), and /or pathogens (viruses or liver flukes), leads to a wound-healing response involving recruitment and activation of inflammatory immune cells, release of cytokines and activation of stromal cells and vasculature. Inflammation and unregulated wound healing promotes cholangiocyte proliferation/survival (transformation) and stromal cell dysregulation (fibrosis). Alterations in signalling pathways through genetic mutations, epigenetic alterations, or post-transcriptional changes in transcription factor activity, as well as genetic variations (SNPs) in bile duct genes involved in differentiation, bile-acid transport, or cholesterol/lipid metabolism all play a part in tumour formation and fibrosis.
PRH proteins are expressed at very low levels in cholangiocytes and are altered in cholangiocarcinoma and in cholangitis.
EXPERIMENTAL METHODS AND RESEARCH PLAN
- Molecular studies: Using RNA sequencing and Global ChIP sequencing we will investigate the consequences of bile acids, cytokines and stromal cells (fibroblast cell lines, primary mesenchymal cells and hepatic stellate cells from isolated bile ducts) in co-culture with cholangiocytes and CCA cells on (i) PRH expression, (ii) global gene expression and (iii) histone modifications at genes encoding cell adhesion molecules such as E-cadherin.
- In vivo model: We will use a mouse model that closely reflects human cholangitis and CCA development. Immunohistochemistry (IHC) of the tumours will allow analysis of stromal, vascular and immune cell changes that accompany tumourigenesis. We will examine the role of PRH in the development of CCA in this model.
- Fibroblasts from xenografts: The role of primary cancer associated fibroblasts (CAFs) on PRH expression will be investigated. We will examine cholangiocarcinoma cell lines grown in co-culture with mesenchymal progenitor cells. We will also examine PRH in patient derived xenograft CCAs when grown in co-culture with mesenchymal progenitors.
- Identification of new extracellular signalling pathways involved in both cholangitis and bile duct cancer.
- New treatments including bile acid treatments that control cholangiocyte survival and proliferation and stromal cell proliferation and fibrosis.
- Gene expression changes that accompany alterations in PRH.
- Development of co-culture and organotypic models for fibrosis and CCA.
Applicants should have a strong background in Cell and Molecular Biology or Biochemistry, and ideally a background in Cancer Biology. They should be able to demonstrate excellent analytical skills and communication skills. They should have a commitment to research in Molecular Sciences and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in a relevant subject.
Due to the nature of funding attached to this studentship we are not able to accept applications from overseas applicants
Gaston K, Tsitsilianos MA, Wadey K, Jayaraman PS. Misregulation of the proline rich homeodomain (PRH/HHEX) protein in cancer cells and its consequences for tumour growth and invasion. Cell & bioscience 2016; 6: 12.
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