Structure-function studies of defective excitatory and inhibitory transmission in neurological disease
Synapses releasing the neurotransmitters GABA, glycine and glutamate play essential roles in health and disease, with defects in synaptic and tonic inhibition resulting in diseases such as autism, idiopathic generalised epilepsies, intellectual disability and startle disease. With the advent of high-throughput exome and genome sequencing technologies, numerous rare sequence variants not present in the general population are being discovered and often published with very little in the way of functional validation to prove pathogenicity. This project will integrate new approaches for testing novel sequence variants found in genes encoding pre- and post-synaptic components of inhibitory and excitatory synapses (e.g. ligand-gated ion channels, neurotransmitter transporters, clustering proteins) using bioinformatics, molecular modelling, molecular biology and electrophysiological assays
The PhD student will be jointly supervised by Professor Robert J Harvey at UCL School of Pharmacy and Professor Trevor G Smart from the UCL Research Department of Neuroscience, Physiology & Pharmacology. The successful candidate will receive cross disciplinary training in molecular biology, cellular biochemistry, molecular modelling, imaging methods and electrophysiology. The supervisors have an extensive collaborative track record in structure-function studies of ligand-gated ion channels and neurotransmitter transporters (e.g. Harvey et al 2004, Science 304:884-887; Rees et al 2006, Nat Genet 38:801-806; Manzke et al 2010, J Clin Invest 120:4118-4128).
The PhD student will be trained in how to generate expression constructs, conduct site-directed mutagenesis, structural homology modelling of receptors and/or transporters, perform bioinformatics analysis (SIFT, PolyPhen) and prioritise mutations for further modelling and functional assays.
Supervisor: Prof. Robert J Harvey
The successful applicant will be expected to have a UK Bachelor’s degree in Pharmacy, Pharmacology, Biology, Biochemistry, Molecular Biology or Genetics, awarded with first or upper second-class Honours, or an overseas qualification of an equivalent standard from a recognised higher education institute, or a recognised taught Master’s degree is required.
Applications must include CV, personal statement plus the contact details of two referees and should be sent to Victor Diran (firstname.lastname@example.org).
Impact Studentship: £15,590