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UCL Department of Neuroscience, Physiology and Pharmacology, Division of Biosciences, Faculty of Life Sciences

NPP academic/Fellowship/support staff or researcher/technician vacancies and PhD studentship opportunities are posted as well when available on the UCL HR website:- http://www.ucl.ac.uk/hr/jobs/index.php

PhD Studentship:  below advert also appears in FindAPhD at http://www.findaphd.com/search/ProjectDetails.aspx?PJID=62757&LID=1001

Title: UNDERSTANDING F508del-CFTR RESCUE: SETTING FOUNDATIONS FOR PHARMACOTHERAPY TO TREAT CYSTIC FIBROSIS

University College London

Department of Neuroscience, Physiology and Pharmacology

Lead PhD Supervisor: Dr Paola Vergani (p.vergani@ucl.ac.uk)

Co-Supervisor: Prof. Peter Tieleman, University of Calgary

Application Deadline: 19th April 2015

Funding Availability: Funded PhD Project (European/UK students only)

Background

Cystic fibrosis (CF) is the most common fatal inherited disease, affecting approximately 10,000 children and young people in the UK alone. It is caused by a defect in CFTR, a channel protein that provides a gated pathway for anions to cross cell membranes. The most common defective CFTR channel is F508del, present in ~90% of patients. F508del-CFTR channels very easily acquire a “misfolded” shape, and are targeted for degradation within the cell. Only a small fraction of F508del channels reach their correct position in the cell membrane. In addition, these spend too much time with their gate closed. Efficient pharmacotherapy for these patients will need to improve all aspects of F508del malfunction.

Research Project

The project at UCL is part of a Strategic Research Centre (SRC) comprising five European laboratories, funded by the Cystic Fibrosis Trust (see: http://www.cysticfibrosis.org.uk/news/new-grants-focus-on-genes-and-data). The general aim of the SRC is to investigate F508del CFTR, and possibly identify drug candidates capable of reducing its defects. The UCL project has three specific aims. As a first step, you will use fluorescence assays recently developed in our lab to screen second site mutations, in cis with F508del, to identify “revertant” mutations capable of rescuing the F508del’s folding and/or gating defects (aim 1). For aim 2, you will work with Prof. Tieleman and his group. The results of aim 1 will be used to validate or improve models of CFTR and F508delCFTR atomic structure. Using computational techniques, you will investigate structural changes induced by revertant mutations that effectively rescue F508del-CFTR. Finally, using patch-clamp techniques, you will investigate how revertant mutations (as well as the most promising drug candidates, identified in partner SRC labs) alter protein movements that open and close the ion channel (aim 3). Combined, these studies will improve our understanding of how CFTR works and why F508del-CFTR malfunctions. Such knowledge will provide foundations for the discovery of better drugs to treat the most common form of cystic fibrosis.

Techniques

Basic molecular biology techniques and fluorescence image acquisition and analysis (aim 1); protein structure prediction methods such as homology modelling, and molecular dynamics simulations (aim 2); heterologous expression and patch-clamp analysis of ion channel function (aim 3).

Studentship

The award provides a very generous tax-free stipend (£22,278, £24,093 and £26,057 during the 3 PhD years) and covers tuition fees (at home/EU student rates).

Requirements

Applicants will need to have a good University degree in a relevant discipline. Students with backgrounds in chemistry, mathematics, or the physical sciences are encouraged to apply in addition to biologists with a keen interest in quantitative analysis. Pending confirmation, the student may be part of the CoMPLEX MRes (https://www.ucl.ac.uk/complex) undergoing a first year of rigorous training in quantitative biology (September 2015 - August 2016). Available funding only covers Home/EU fees.

Further details and application procedure

For more information and informal enquiries, please contact Dr Paola Vergani (p.vergani@ucl.ac.uk). To apply, send her a CV, contact details of two referees, and a personal statement describing your reasons for applying and your research interests. Please note that applications will be assessed and interviews arranged as they are received, so the studentship may be filled before the deadline.

References

1. Lukacs GL, Verkman AS. CFTR: folding, misfolding and correcting the [delta]F508 conformational defect. Trends Mol Med 2012; 18(2): 81-91.

2. Rabeh Wael M, Bossard F, Xu H, et al. Correction of Both NBD1 Energetics and Domain Interface Is Required to Restore deltaF508 CFTR Folding and Function. Cell 2012; 148(1-2): 150-63.

3. Csanády L, Vergani P, Gadsby DC. Strict coupling between CFTR's catalytic cycle and gating of its Cl- ion pore revealed by distributions of open channel burst durations. Proc Natl Acad Sci U S A 2010; 107(3): 1241-6.

4. Vergani P, Gadsby D, Csanády L. CFTR, an Ion Channel Evolved from an ABC Transporter. In: Roberts GCK, ed. Encyclopedia of Biophysics. Berlin Heidelberg: Springer 2013: 254-65. (open access version: http://discovery.ucl.ac.uk/1403738/)