Allosteric modulators of ligand-gated ion channels as insecticides with novel modes of action

Prof. Neil Millar Department of Neuroscience, Physiology and Pharmacology, University College London
Mr James Goodchild, Syngenta

Project Description

Ligand-gated ion channels (LGICs) are a diverse family of neurotransmitter receptors in both vertebrate and invertebrate species. The Millar lab at UCL has extensive experience in combining molecular biological, pharmacological and electrophysiological techniques to examine human and insect LGICs. Human LGICs are major targets for therapeutic drug discovery for a variety of neurological and psychiatric disorders. In insects LGICs are important target sites for insecticides that are used extensively in areas such as crop protection and animal health. A focus of recent research in our laboratory has been the characterisation of compounds that modulate the functional properties of LGICs by interacting with sites other than the conventional (orthosteric) agonist-binding site (allosteric modulators). For example, our recent studies of mammalian LGICs have included the characterisation of novel positive allosteric modulators (PAMs), negative allosteric modulators (NAMs) and allosteric agonists (see, for example: Young et al. 2008; Gill et al. 2011, Gill et al. 2012; Lansdell et al. 2014; Chatzidaki et al. 2015; Gill-Thind et al. 2015). This PhD project will extend our previous studies concerning allosteric modulation of mammalian LGICs by examining the structurally related family of insect LGICs.



The primary aim of this studentship will be to undertake a detailed molecular pharmacological investigation of the mechanism of action of allosteric modulators. This will be achieved by combining molecular biological, pharmacological and electrophysiological techniques. The project will focus on the family of pentameric LGICs that includes receptors for neurotransmitters such as acetylcholine (ACh) and γ-aminobutyric acid (GABA). Work will focus largely on studies of cloned LGICs but is also expected to include electrophysiological studies of native LGICs. One of the aims of the project is to evaluate the hypothesis that allosteric modulators of insect LCICs may provide an opportunity to develop new insecticides with novel modes of action and with greater species selectivity. An additional recent focus of research in our laboratory has been to understand the mechanisms by which insecticide resistance can develop as a result of mutations in insect LGICs (see, for example: Liu et al. 2005; Puinean et al. 2013; Wang et al. 2016; Zhang et al. 2016). Consequently, a further motivation for this project is the hope that allosteric modulators of LGICs may have insecticidal activity but be unaffected by existing mechanisms of insecticide resistance.

This CASE studentship will provide an opportunity for the student to gain valuable experience by spending a period of time (typically 3 months or longer) working with our industrial partner Syngenta in their research facility at Jealott’s Hill, Bracknell.



References

  • Chatzidaki et al. (2015) Neuropharmacol. 97, 75-85.
  • Gill et al. (2012) Mol. Pharmacol. 81, 710-718.
  • Gill et al. (2011) Proc. Nat. Acad. Sci. USA 108, 5867-5872.
  • Gill-Thind et al. (2015) J. Biol. Chem. 290, 3552-3562.
  • Lansdell et al. (2015) Mol. Pharmacol. 87, 87-95.
  • Liu et al. (2005) Proc. Nat. Acad. Sci. USA 102, 8420-8425.
  • Puinean et al. (2013) J. Neurochem. doi: 10.1111/jnc.12029.
  • Wang et al. (2016) Insect Biochem. Mol. Biol. 71, 29-36.
  • Young et al. (2008) Proc. Nat. Acad. Sci. USA 105, 14686-14691.
  • Zhang et al. (2016) Sci. Reports 6, 32335. doi: 10.1038/srep32335.

Application

Applicants must hold, or be expected to achieve, a first or high upper second-class undergraduate honours degree or equivalent (for example BA, BSc, MSci) or a Masters degree in a relevant subject. Interested applicants are encouraged to contact Neil Millar (n.millar@ucl.ac.uk) in advance of the deadline, 20th January 2017 at 5pm.


To apply you will need to send the following documents in a single email to: LIDo.Admissions@ucl.ac.uk. All documents must be submitted in unprotected PDF format.


  • Completed Application Form (Sections A and B) including details of two Academic References
  • The disability and ethnic origin monitoring form
  • Official Final Transcripts from Completed Programmes of Study
  • Official Interim Transcripts from On-going Programmes of Study
  • English Language Qualification (if required, please see below)
  • Academic CV
  • Copy of Passport

Please click the relevant links below to download a zipped folder of application documents in your preferred format.
Application Pack (Word).zip
Application Pack (PDF).zip