A Tr(i)p to Chronic Pain

Chronic pain such as chronic arthritis pain is debilitating and disabling. In the UK, over one third of the population are afflicted with chronic pain, incurring enormous medical costs and loss of productivity and jobs in the workplace. Considerable need is required to understand how chronic pain is evolved and maintained for developing desirable pain therapies. The Ph.D studentship provides you a promising Trip to delve into this widespread health problem meanwhile developing comprehensive research skills.

In brief, chronic pain results from abnormal pain signal generation, transmission and processing in the peripheral and central nervous systems. Many ion channels and signaling messengers have been implicated. Notably, Transient Receptor Potential (Trp) channels have stood out to be a prominent player and are involved in multiple processes of chronic pain. One member of the Trp channel family called TRPA1 is particularly interesting. It acts as a chemosensor responsible for detecting irritating and pungent chemicals crucial to chemical induced pain. Apart from chemo nociception, TRPA1 has also been involved in transducing mechanical and cold pain in different types of chronic pain conditions. But puzzlingly, TRPA1 alone is not a direct receptor for mechanical and cold stimuli, suggesting additional unknown entities or mechanisms are involved in this process. The Ph.D project aims to dissect out the mechanisms by which TRPA1 transduces noxious mechanical and cold pain. This special Trp channel will form the trip to your PhD.

We have made major achievements towards this goal. An interesting our finding is that TRPA1 forms a macro signaling complex with the scaffolding protein IQGAP1 which acts a signaling hub coordinating a diversity of intracellular signaling. We will first investigate whether IQGAP1 is the long-sought unknown protein required for TRPA1-mediated mechanical and cold pain. We will then examine the downstream targets of TRPA1 signaling. For these experiments, we will test the role of voltage-gated K+ channels, known critical to nerve firing, in mechanical and cold pain. We will finally define the intermediate signaling messengers that couple TRPA1 channels to the downstream targets.

To achieve the aims, a combined methodology will be used including electrophysiology, cell culture, live cell imaging, histology, protein biochemistry, Western blotting, qPCR, molecular biology, gene transfections, transgenic mice breeding and animal behaviours. You will be supported by senior scientists in a vibrant and stimulating environment.

References:

1. Hasan R and Zhang X. Ca2+ regulation of TRP ion channels. Int J Mol Sci. 19(4), 2018.
2. Manolache A, Babes A and Babes R. Mini-review: The nociceptive sensory functions of the polymodal receptor Transient Receptor Potential Ankyrin Type 1 (TRPA1). Neuroscience Letters 2021.
3. Briggs MW and Sacks DB. IQGAP1 as signal integrator: Ca2+, calmodulin, Cdc42 and the cytoskeleton. 542(1-3), 2003, 7-11.
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BBSRC Strategic Research Priority: Understanding the rules of life – Neuroscience and Behvaiour.

Techniques that will be undertaken during the project:

Electrophysiology, cell culture and transfection, live cell imaging and confocal imaging, histology, protein biochemistry, Western blotting, qPCR, molecular biology, transgenic mice breeding and animal behaviours