PhD Studentship: Investigating the Biological Basis of Sex Differences in Nociceptor Excitability with Age-related Joint Degeneration

This PhD aims to determine the biological basis of sex specific mechanisms of nociceptor hyperexctaibility in age-related joint degeneration. The proposal addresses the biology of ageing, the long-term condition of joint degeneration and the consequent burden of pain, which fit the BBSRC remit of ‘securing better health, ageing and wellbeing.’ 

Ageing is associated with joint degeneration that can lead to increased excitability of articular nociceptors and consequent pain. However, the impact of ageing itself on the excitability of articular nociceptors is unknown. Moreover, females are at higher risk of age-related joint degeneration, although mechanisms underlying sex differences in associated pain sensitivity are unclear. 

A major hurdle in effective translation of preclinical studies addressing the biology of age-related joint degeneration is the availability of clinically relevant rodent models. Preliminary data generated in our lab demonstrates that the menisco-ligamentous injury model in mice leads to substantial cartilage loss and behavioural hypersensitivity (to mechanical and cold stimuli), which mimics the clinical picture of age-related joint degeneration and associated changes in pain sensitivity, in a sex dependent manner. 

The rationale of this project is based on 2 overarching questions: (1) How does age-related joint degeneration cause increased pain sensitivity and sex differences in pain? Pain sensitivity may be mediated by hyperexcitable nociceptors that innervate the degenerative joint (e.g. subchondral bone), or through cross talk of primary sensory neurons (e.g. through gap junctions in dorsal root ganglia). (2) Can modulation of the neuro-immune axis affect nociceptor excitability mediated by age-related joint degeneration? We will test the hypothesis that targeting the neuro-immune axis can modulate nociceptor excitability in age-related joint degeneration, either directly or indirectly via inter-cellular communication. 

Key techniques will involve in vivo microCT imaging for bone morphology, In vitro calcium imaging of primary sensory neurons, immunophenotyping and cell sorting, as well as pain behaviour assays and the use of transgenic mice for in vivo studies. This PhD is an iCASE studentship in collaboration with GSK. 

Aim 1. Determine whether bone morphological changes with age-related joint degeneration drive sex differences in the development of pain sensitivity. 

Aim 2. Determine whether sex differences in pain sensitivity following age-related joint degeneration are mediated directly by changes in neuronal excitability of articular afferents or via neuro-immune cross-talk within dorsal root ganglia 

Aim 3. Test the mechanistic role of specific immune cells on articular nociceptor hyperexcitability in age-related joint degeneration

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