Molecular Mechanisms for a Novel Class of Openers Targeting Voltage- and Calcium-activated Potassium Channels.

We are seeking a PhD student with a strong interest in molecular and cellular biology. The post-holder would work on a project aiming to define the molecular target and mechanism of action of novel compounds developed by Canbex Therapeutics for the treatment of neurological disorders. The project is funded by a strategic award of the MRC (4-year PhD MRC-CASE studentship award).

Supervisors:
Martin Stocker, Neuroscience Physiology and Pharmacology Department, University College London, London WC1E 6BT, UK; David Selwood and Keith Powell, Canbex Therapeutics.

Brief Summary of Project:
Background:
Fragile X syndrome (FXS) is the most common inherited form of mental disability. A novel class of compounds synthesized by Canbex Therapeutics shows beneficial effects on cognitive and behavioural deficits in an animal model of FXS. Additionally, these compounds have shown positive effects in the treatment of spasticity in a multiple sclerosis model, acting through the activation of voltage- and calcium-dependent potassium channels (BK channels). BK channels are widely expressed in the nervous system where they contribute to the repolarization of action potentials and afterhyperpolarization in neurons, beside regulating synaptic release of neurotransmitters. Their molecular make-up depends on the co-assembly of alpha, beta and gamma subunits that confer specific kinetic and pharmacological properties to the channels. BK channel dysfunction has been proposed to contribute to the neurological deficit in FXS.

Aims:
The main aim of this project is to define the molecular target and mechanism of action of the novel compounds develop by Canbex Therapeutics and optimise drug design for the treatment of neurological disorders. The results of this project will ultimately enable us to achieve the best possible pharmacological approach to the treatment of spasticity in multiple sclerosis and other neurological disorders that can be treated by targeting neuronal voltage- and calcium-dependent potassium channels, such as Fragile X syndrome.

Plan of investigation:
The action of the Canbex compounds will be studied by electrophysiology and in vitro pharmacology on recombinant and neuronal BK channels. On one hand, their effects will be investigated at the level of single neurons and whole circuits in brain slices from healthy and FXS-model animals. On the other, the identification of their molecular mechanism of action and primary target will lead us to define and model their binding site and potentially design, synthesize and test optimised derivatives.
We look for a student with a strong background in molecular and cellular biology and with excellent analytical skills, to be trained in molecular biology, electrophysiology on cell lines and neurons, in vitro pharmacology, drug synthesis and design, and computational and in silico modelling. The student will receive broad scientific training in a multidisciplinary environment, gaining valuable experience both in an academic and in an industrial setting.

Eligibility: this award funds home/EU UCL fee level and London minimum stipend of £16K (living costs, this stipend is not taxed) for 4 years. To apply, you need to hold an undergraduate or Masters degree (at least 2:1 or equivalent) and meet the MRC residency criteria (see URL below for detail) UK residents are eligible for a full award (fees plus maintenance stipend). EU residents may be eligible for a fees-only award (see below) but must provide proof of sponsorship or the ability to self-support maintenance costs for the duration of the award.
(http://www.mrc.ac.uk/skills-careers/studentships/studentship-guidance/student-eligibility-requirements/). Applicants who do not fulfill these criteria are not eligible. 

Programme start date: 26th of September 2016
Informal enquiries to: Dr Martin Stocker: [Email Address Removed]

Application procedure: Applications must be made through UCL Admissions via the link below. Applicants should select the programme RRDBISSNPP01 PhD Neuroscience, Physiology and Pharmacology and complete the application as per the guidelines. Automated reference requests will be sent to the referees named in the application only once it has been submitted. Applicants must ensure that references are sent by the application deadline below in order for the application to be considered. Please note that this means that your must submit your online application as early as possible to give your referees sufficient time to respond to the automated reference request.
http://www.ucl.ac.uk/prospective-students/graduate/apply

Closing date: Midday, 31st May 2016
Shortlisted candidates only will be notified by e-mail - interviews will be conducted in the week commencing on June 6th.