PhD in Pathophysiology and Repair, Cardiff School of Biosciences
Reference Number: R1055
Key Studentship Information
Project title: Molecular and functional characterisation of the nutri-epigenetic effects of chemopreventative polyphenols in intestinal cancer
Project description: Epigenetic modifications, such as DNA methylation patterns at CpG sites and the deregulation of chromatin states has emerged as a major governing factor in tumour initiation, progression and cancer therapy sensitivity. Various environmental factors such as diet, behaviour, stress, and toxins remodel our epigenome either in a beneficial or detrimental way. Since DNA methylation is reversible in contrast to genetic defects, chemopreventive nutritional polyphenols such as soy, genistein, resveratrol, and catechin are currently being evaluated for their ability to reverse adverse epigenetic modifications in cancer stem cells in order to attenuate tumorigenesis. Although polyphenols in fruit and vegetables have chemopreventative properties, the specific molecular mechanisms are still unclear. Several recent studies have confirmed the chemopreventative properties of curcumin and edible berries both in vitro and in vivo.
Both black raspberries and curcumin have been shown to inhibit chemically-induced tumorigenesis in the rodent colon and were shown to be effective at both the initiation and the progression stages of tumour development. Further studies have shown that 12-week feeding of a diet containing 10% freeze-dried black raspberries significantly inhibited intestinal tumour formation in two murine models of human colorectal cancer. In this study a model of Wnt-driven tumorigenesis showed a 60% reduction in tumour number after black raspberry administration, which was shown to occur through the effects of the berries on aberrant ß-catenin signalling. Furthermore a Phase I pilot study demonstrated that black raspberries reactivated silenced Wnt pathway antagonists by promoter demethylation through DNA methyltransferase inhibition, which resulted in a decrease in proliferation, apoptosis, and angiogenesis. Curcumin has also been shown to decrease ß-catenin signalling in vitro, and has been shown to reduce tumour formation in a murine model of human Wnt-driven tumorigenesis. Recent work has also demonstrated the potential role of curcumin as an epigenetic agent and has shown a vital role for this chemopreventative compound in the regulation of epigenetic modulators.
In this study we will investigate the mechanism of the chemopreventative properties of dietary polyphenols such as those found in black raspberries and curcumin on Wnt-driven tumorigenesis. Initial work will characterise the effect of polyphenols on aberrant Wnt signalling and intestinal homeostasis in the mouse small intestine. We will also assess the effect of polyphenols on the intestinal stem cell population and the initiation of adenoma formation. Furthermore we will investigate the potential epigenetic mechanism of these active dietary constituents by analysing the expression levels of key tumour suppressor genes that are known to be epigenetically regulated in intestinal tumorigenesis.
Eligibility and Funding
This studentship funded by Tenovus will start on 1st October 2013. The stipend, per annum, is at least £13,726.
This studentship is open to applicants worldwide although overseas applicants would need to fund the difference between the UK/EU tuition fees and the overseas tuition fees.
Applicants need a 2:1 in their undergraduate degree or a 2:2 plus Master's/Master of Research in a relevant subject (or foreign equivalents).
How to Apply
Applications for this PhD studentship can be made through our Online Application Service. Please ensure you state in the 'Funding' section of the application that you intend to apply for this studentship.
For further information, please contact Swapna Khandavalli by email on KhandavalliS@cardiff.ac.uk or on +44 (0)29 2087 5243.