Work Package 3:
Molecular pathways leading to neuropathic pain
1) To perform both targeted and genome wide transcriptional profiling in tissues derived from neuropathic pain patients.
2) To integrate data from pain risk associated gene variants and transcriptional profiling in order to build protein networks for signalling pathways implicated in pain.
3) To investigate the functional role of pain risk associated genes using in silico prediction and cellular systems.
Description of work
We will utilise significant and existing bioinformatic resources, gene expression studies and cellular models in order to further understand the functional role of gene variants and pathways associated with neuropathic pain risk (in WP2). This work package will be led by David Bennett (Oxford). We will utilise existing Biobanks to facilitate this process. This includes DNA, RNA, serum and urine from participants in Generation Scotland and GoDARTS (Dundee). The Pain in Neuropathy study (Oxford, Imperial) includes storage of Plasma and RNA extracted from whole blood and fresh frozen skin biopsy from distal leg currently from 320 participants stored in secure, monitored -80 freezers in Oxford. This is linked to clinical, sensory testing and gene sequence in an anonymised fashion. The Thomas Willis brain bank Oxford is now collecting human fresh frozen post mortem DRG and spinal cord tissue with validated RNA quality sufficient for gene expression studies. The IMI StemBANCC consortium is generating a bank of human iPS cells from patients both with monogenic pain disorders as well as complex neuropathic pain conditions such as diabetes mellitus which will be available in order to develop cellular models.
- Rare sodium channel variants associated with painful diabetic neuropathy
- The novel activity of carbamazepine as an activation modulator of the NaV1.8-S242T mutant channel
- Defining the functional role of sodium channel NaV1.7 in human nociception
- Analysis of RNA expression in dorsal root ganglions after peripheral nerve injury
WP leader: University of Oxford