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Validating the molecular mechanisms of Chinese herbal remedies employing a novel non-animal model

  • Full or part time
  • Application Deadline
    Tuesday, January 31, 2017
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Modern medical research often focuses on the identification of new compounds for therapeutic treatment followed by extensive toxicological and safety testing. In many cases this costly development and testing process fails in human trials. An alternative approach in this research is to investigate ethnobotanical remedies that have been extensively used to improve health and in the treatment of diseases in different parts of the world. In these cases, despite a history of use, Western medicine is often slow to engage with the treatments since they do not have a validated mechanisms of action, and without this rationale for use, are rarely tested in clinical trials.

Our research has demonstrated the successful use of a simple model system for identifying mechanisms of action and primary targets of natural products and therapeutic compounds. Compounds include the anti-epileptic compound valproate (valproic acid, Depakote, Divalproex), components of the ketogenic diet, tastants, and flavonoids. In these studies, understanding the biochemical effect of compounds within cells, identifying mutants resistant to these effects and characterising this resistance has helped describe how the compounds work and has supported the validation of the compounds in health and medical research.

This project will involve the analysis of specific components of herbal remedies arising from hundreds of years of human use. We have identified a number of compounds that have strong activity in the simple model, at concentration ranges often used in research, suggesting that the compounds have targets in the model. The project will involve the characterisation of three active components of these traditional remedies and the identification of genes controlling the effect of the compounds. Characterisation of these proteins, and their role as targets for each compound will help to explain their health and medicinal properties.

The model system that we employ for research is the social amoeba, Dictyostelium discoideum. This simple system provides a range of advantages for research including: rapid growth and development; screening procedures for pharmacogenetics studies; gene ablation and overexpression in isogenic lines; a range of orthologues to human proteins; and heterologous gene expression for studies on human proteins. In addition, this model represents an excellent example of 3Rs research, where advance health and medical research can be carried out without the loss of animal life. Our laboratory has championed this approach.

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).

Funding Notes

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.

References

1. Chen P E, Geballe M T, Katz E, Erreger K, Livesey M R, O'Toole K K, Le P, Lee C J, Snyder J P, Traynelis S F and Wyllie D J. Modulation of glycine potency in rat recombinant NMDA receptors containing chimeric NR2A/2D subunits expressed in Xenopus laevis oocytes. (2008) Journal of Physiology. 586:227-45.

2. Wrighton D C, Baker E J, Chen P E and Wyllie D J. Mg2+ and memantine block of rat recombinant NMDA receptors containing chimeric NR2A/2D subunits expressed in Xenopus laevis oocytes. (2008) Journal of Physiology. 586:211-25.

3. Erreger K, Geballe M T, Kristensen A, Chen P E, Hansen K B, Lee C J, Yuan H, Le P, Lyuboslavsky P N, Micale N, Jorgensen L, Clausen R P, Wyllie D J, Snyder J P and Traynelis S F. Subunit-specific agonist activity at NR2A-, NR2B-, NR2C-, and NR2D-containing N-methyl-D-aspartate glutamate receptors. (2007) Molecular Pharmacology. 72:907-20.

4. Wyllie DJA and Chen PE. Taking the time to study competitive antagonism. (2007) British Journal of Pharmacology.150: 541-51.

5. Frizelle PA, Chen PE and Wyllie DJA. Equilibrium constants for NVP-AAM077 acting on recombinant NR1/NR2A and NR1/NR2B NMDA receptors: implications for studies of synaptic transmission. (2006) Molecular Pharmacology. 70: 1022-1032.

6. Chen PE and Wyllie DJ. Pharmacological insights obtained from structure-function studies of ionotropic glutamate receptors. (2006) British Journal of Pharmacology. 147:839-53.

7. Chen PE, Geballe MT, Stansfeld PJ, Johnston AR, Yuan H, Jacob AL, Snyder JP, Traynelis SF and Wyllie DJ. Structural features of the glutamate binding site in recombinant NR1/NR2A N-methyl-D-aspartate receptors determined by site-directed mutagenesis and molecular modeling.(2005) Molecular Pharmacology. 67:1470-84.

How good is research at Royal Holloway, University of London in Biological Sciences?

FTE Category A staff submitted: 24.00

Research output data provided by the Research Excellence Framework (REF)

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