McNaughton Lab projects
Major area 1: Involvement of HCN2 ion channels in inflammatory and neuropathic pain
Role of HCN channels in chronic pain (funded by Arthritis Research UK, Brain research UK and Merck Inc).
Can chronic pain be abolished long after initiation? We will use genetic and pharmacological approaches to investigate this question in pain caused by nerve damage, migraine and arthritis. With clinical colleagues we are investigating whether HCN ion channel blockers are effective humans in a volunteer model of neuropathic pain and in neuropathic pain patients.
Small-molecule inhibitors of HCN2 (In collaboration with Merck Inc)
We are using medicinal chemistry to develop HCN2 selective drugs as novel analgesics. We then test these new drugs in animal models of pain, followed by entry into human clinical trials
Major area 2: The heat-sensitive ion channel TRPV1 as a target in inflammatory and neuropathic pain
Novel analgesics based on AKAP79/TRPV1 antagonism (funded by BBSRC).
We have found that a scaffolding protein, AKAP79, interacts with a heat-sensitive ion channel, TRPV1, and that this interaction is important in pain. We will discover the structure of the binding site between TRPV1 and AKAP79, and we will use this structure to identify small-molecule “hits”. We will then test these hits in vivo and develop as novel drugs.
Major area 3: Novel thermally-sensitive ion channels
Ion channels controlling thermoregulation (funded by BBSRC).
We have found that previously unknown thermally-sensitive ion channels are expressed in sensory neurons both in the periphery and in the central nervous system. We will use RNA sequencing to discover their molecular identity. We will then find out how these ion channels control the regulation of body temperature.
Major area 4: Direction-finding by neutrophils
Neutrophils must navigate to sites of injury and infection in order to engulf and kill bacteria and to initiate tissue repair. Recent evidence shows that hydrogen peroxide is an important guidance molecule, but how neutrophils sense a gradient of hydrogen peroxide is currently unknown. We are exploring some new ideas about the coupling mechanisms between hydrogen peroxide and neutrophil navigation.
The main techniques in use in the lab are:
- Patch clamp electrophysiology
- Calcium imaging
- Confocal microscopy
- Fluorescence microscopy
- Molecular biology
- Cell culture
- Creation of transgenic mouse strains
- Animal behavioural experiments