PhD studentship investigating glycine metabolism in the human brain.

Although not yet officially advertised, we hope to have a successful student appointed to start in April 2016.

In the mean time interested potential candidates should email Mark Poolman mgpoolman AT brookes DOT ac DOT uk for further details.

Project Description:

Bacground:

This project is generously funded by the Moscow Institute of Cytochemistry and Molecular Pharmacology (ICMP) and is the result of previous collaboration between Prof. Yaroslav Nartsissov of ICMP, and Prof. David Fell and Dr. Mark Poolman from Oxford Brookes University

Introduction:

The amino acid glycine is a neurotransmitter which is the agonist of the inhibitory GlyR receptor, localised in the spinal cord, brain-stem and other sub-cortical structures of the human brain. It has been shown to interact with a number of psycohactive compounds including anaesthetic and analgesic agents, cannabinoids and alcohol. There is, therefore, an interest in understanding the mechanisms by the concentration of glycine in the post-synaptic cleft may be regulated and controlled, and the potential impact that such modulation has upon GlyR. This is to be investigated using an integrated combination of experimental and computational approaches.

Computational Modelling:

The total glycine-bound GlyR (and hence the inhibitory GlyR Chloride ion current) is determined by its affinity for glycine and the steady-state concentration of glycine in the synaptic cleft. This in turn is determined by the rate of production by neighbouring glial cells and from the immediate cellular environment, and the rate of uptake by the specific GlyT1 transporter, also found in neighbouring glial cells.

Starting with an existing kinetic model of GlyR in isolation, these processes will be represented in the form of a mathematical model and analysed with our in-house software package, ScrumPy - Metabolic Modelling in Python, to assess the contribution of each of these processes to the final amount of glycine-bound GlyR and its associated Chloride ion current.

A second strand to the computational part of the project will be to investigate de-novo synthesis of glycine, a pathway not well determined in the nervous system. A previous student from ICMP, during a period of secondment at OBU, constructed a draft genome-scale model (GSM) of human metabolism that could account for glycine synthesis. This model will be refined and analysed to identify potential metabolic responses to variation in glycine demand or potential stress factors (e.g. hypoxia, hyopglycaemia) with the ultimate goal of integrating the two models.

Experimental - short term effects of varying glycine concentration:

GlyR will be expressed in Xenopus oocytes and its electrophysiological response to varying glycine concentrations determined in the Bermudez lab. These results will determine the kinetic parameters for the modelling work and identify the increase in glycine concentration in the synaptic cleft required to achieve a realistic physiological effect.

Experimental - long term effects of varying glycine concentration:

In addition to the obvious potential short-term effects of glycine, the project will test the hypothesis that long term exposure to elevated glycine increases the expression of GlyR in CNS neurons. This will be achieved by exposing cultured human embryonic kidney (HEK) cells to a range of glycine concentrations and subsequent GlyR activity determined, again in the Bermudez lab. Any changes in Gly expression will again be incorporated into the model and their effect on the target level of glycine enhancement calculated.