Flavonoids are a group of chemicals found in plants that are commonly consumed in the human diet. Although a large body of evidence has demonstrated that the consumption of flavonoid-rich foods is associated with positive health benefits, a direct role for these natural products in health remains controversial. Wide ranging in vitro studies have also suggested a role for flavonoids in the treatment of numerous conditions including inflammation, cancer, cardiovascular disease, and in other health related areas such as improvements in memory and learning. Although these compounds are often considered to act through an anti-oxidant effect, they are increasingly being recognised as causing specific effects on cell proteins, where the specific molecular mechanisms (and protein targets) for these effects remain largely unknown.
Our studies provide world-leading examples of using the simple eukaryote, Dictyostelium, as an innovative animal-replacement model in a range of studies relating to biomedicine, natural products pharmacogenetics, and molecular pharmacology (6). Examples of our breakthroughs include:
a) Identifying the molecular mechanism of the epilepsy treatment valproic acid in Dictyostelium (Chang et al 2012; Chang et al 2014; Cunliffe et al 2014) and the translation of this to in vitro and in vivo animal models (Chang et al 2014), leading to the identification novel potent compounds with efficacy in multiple animal models (Chang et al 2014; Chang et al 2015), with two resulting patents (WO_2012069790_A1, GB_Application_1416017.0) and the discovery of the target of decanoic acid in epilepsy control (Chang et al 2016; Walker and Williams 2016). Two clinical trials relating to this discovery are currently in progress.
b) Identifying targets for bitter tastants related to drug development and therapeutic activity (Robery et al 2011; Robery et al 2013; Cocorocchio et al 2016).
c) Illustrating the conserved roles of homologues of health/disease related human proteins (Ludtmann et al 2014; Waheed et al 2013; Otto, Sharma and Williams 2016).
These studies suggest that Dictyostelium can inform our understanding of cellular functions of food relevant to human health.
This project will involve the investigation of three health-related flavonoids to identify molecular mechanisms of action for each. We have demonstrated that these flavonoids are active in Dictyostelium as a model system. This approach involves screening a Dictyostelium mutant library to identify proteins controlling the effect of these food compounds. Flavonoid-dependent changes in cell function will be investigated to identify molecular mechanism of these compounds. In addition cell lines lacking a target that may represent an underlying common mechanism of multiple flavonoids will be examined. Human homologues of the identified proteins will be investigate in Dictyostelium, and mammalian cell lines will be used to provide translational research and may lead to the analysis of human samples.
The project will provide advanced training in a multidisciplinary range of techniques, including cell and developmental biology, biochemistry, pharmacology, and pharmacogenetics and outstanding training in 3Rs research and its broad application. The student will also be trained in traditional (mammalian) cell models, providing a new integrated way of working in 3Rs research, in addition to scientific writing and oral presentation at international meetings (the annual International Dictyostelium meeting).
Applicants should already have or be expected to obtain a First or upper Second Class degree in a relevant discipline. This studentship is fully funded for three years. It covers tuition fees at the UK/EU rate and includes a stipend at the standard Research Council rate (currently £16,296 per annum). Funding is available for UK and EU students.
Otto, Sharma and Williams (2016) Non-Catalytic Roles of Presenilin throughout evolution. Journal of Alzheimer’s disease, 52(4):1177-87.
Otto et al and Williams (2016) Employing Dictyostelium as an advantageous 3Rs model for pharmacogenetic research. In Methods in Molecular Biology: Chemotaxis,1407,123-130.
Chang et al and Williams (2016) Seizure control by decanoic acid through direct AMPA receptor inhibition. Brain, 139(Pt 2):431-43.
Cocorocchio et al and Williams (2016) Bitter tastant responses in the amoeba Dictyostelium correlate with rat and human taste assays. ALTEX, 33(3):225-36.
Walker and Williams (2016) Identifying the molecular mechanism of the MCT (ketogenic) diet. In ‘Ketogenic Diet and Metabolic Therapies: Expanded Roles in Health and Disease’, Oxford University Press edited by Susan Masino. ISBN: 9780190497996
Zuckermann, La Ragione, Baines, and Williams (2015) Valproic acid protects against haemorrhagic shock-induced signalling changes via PPARγ activation in an in vitro model. British Journal of Pharmacology, 172(22):5306-17.
Chang et al and Williams (2014) Seizure control by derivatives of medium chain fatty acids associated with the ketogenic diet show novel branching-point structure for enhanced potency. Journal of Pharmacology and Experimental Therapeutics, 352(1):43-52.
Ludtmann et al and Williams (2014) An ancestral non-proteolytic role for presenilin proteins in multicellular development of the social amoeba Dictyostelium discoideum. Journal Cell Science. 127(7):1576-84.
Cunliffe et al and Williams (2014) Epilepsy Research Methods Update: Understanding the causes of epileptic seizures and identifying new treatments using non-mammalian model organisms Seizure, 24,44-51
Waheed et al, Williams* and Carew* (2013) Naringenin inhibits the growth of Dictyostelium and MDCK-derived cysts in a polycystin-2 (TRPP2)-dependent manner. British Journal Pharmacology.171(10):2659-70.
Robery et al and Williams (2013) A novel human receptor involved in bitter tastant detection identified using the model organism Dictyostelium discoideum. Journal of Cell Science, 126(23):5465-76
Chang, Walker and Williams (2013) Seizure-induced reduction in PIP3 levels contributes to seizure-activity and is rescued by valproic acid. Neurobiology of Disease. 62C:296-306
Chang et al and Williams (2013) Seizure control by ketogenic diet-associated medium chain fatty acids. Neuropharmacology, 69:105-14
Chang et al and Williams (2012) The anti-epileptic valproic acid and other medium chain fatty acids acutely reduce phosphoinositide levels independently of inositol in Dictyostelium. Disease Models and Mechanism,5,115-124.
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FTE Category A staff submitted: 24.00
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