PhD Research Project: Targeting the exocytotic machinery to treat chronic pain.

An early and key event in pain signaling and its subsequent chronification is the increased excitability of peripheral nociceptors and enhanced exocytosis of neurotransmitters. Underpinning this hyper-excitability is the increased trafficking of ion channels to the plasma membrane. Both the delivery of additional ion channels to the membrane and release of neurotransmitters from secretory vesicles is dependent upon vesicular membrane fusion events driven by the assembly of functional SNARE complexes.

Botulinum neurotoxins are endopeptidases that cleave and inactivate SNAREs thereby preventing vesicle fusion. This project aims to explore and develop the therapeutic potential of novel botulinums (nBots), created in the Davletov lab, to produce long lasting block of pain induced hyper-excitability and neurotransmission in nociceptors. While much is known about the SNAREs involved in regulating vesicle fusion during neurotransmitters release, little is known about SNAREs involved in the delivery of ion channels to the plasma membrane in health or disease.
Specific objectives of this project will be to: (1) Use protein engineering to generate bespoke nBots targeted to subpopulations of sensory neurons using receptor-based ligands ( for details see (Arsenault, J., et al. (2013). J Neurochem 126(2): 223-233) (2) Use in vitro methods to evaluate and compare the SNARE cleaving capacity and targeting of nBots with native toxins (3) Perform detailed functional analysis (electrophysiology, live cell imaging) analysis of the effects of selected nBots on inflammation-induced hyper-excitability and ion channel activity in nociceptors in vitro and in vivo.

Funding for this Studentship is provided through an MRC CASE Industrial studentship awarded to EPS/BD at University of Sheffield and Lisa Broad (Eli Lilly and Company, UK). The project is designed to provide the student with experience of collaborative research with a non‐academic partner and offer an outstanding student an experience of two distinct research cultures and provide access to a wider than usual range of technology, facilities and expertise.

As part of the studentship, the student will be expected to spend a minimum of three months with the non-academic partner. Full student support is provided for UK resident students who have been resident in the UK and Islands for the full three-year period before the first day of the first academic year of the course; the main purpose for your residence in the UK and Islands must not have been to receive full-time education during any part of the three-year period.

Funding Notes

Directly funded project European/UK students only.