Title: Role of Rbfox1 in development of osteoarthritis pain: advancing mechanistic studies towards better-quality drug discovery
Funder: Versus Arthritis

Abstract: Pain in osteoarthritis (OA) is a major debilitating symptom, and the main reason for why patients seek medical attention and intervention(1). Current therapeutic strategies provide only poor analgesic control, often involve major surgery and can have significant and very serious side effects, such as myocardial infarction (NSAIDs) (2) and addiction (opioids). A key driver of persistent pain in OA is believed to be hyperactivity in peripheral nociceptive neurons (3), as evidenced by the fact that knee replacement surgery provides pain relief, however not in all occasions. A significant number of individuals report experience of pain after arthroscopy(4). A better understanding of the molecular mechanisms that drive this heightened excitability is therefore urgently needed, especially to improve targeted drug development. We are interested in the role of splicing factor Rbfox1/A2pb1 in mediating maladaptive plasticity of peripheral nociceptors in OA. Genome wide association studies (GWAS) studies have linked a risk variant in the Rbfox1 gene to hand osteoarthritis in a UK Twin study(5) and an independent Finish female cohort (6). As an alternative splicing factor, Rbfox1 influences an extensive gene regulatory network, favouring expression of specific isoforms of molecules that are important for neuronal excitability. Indeed, it is thought that Rbfox1 is central to regulating the balance and adaptation of neuronal circuit to activity changes. Many of its targets are genes that participate in sensory processing or are linked to chronic pain. We therefore hypothesise that Rbfox1 plays a critical role in peripheral sensitisation through favouring isoforms of a subset of pain genes that create heightened nociceptor responsivity. We aim to identify specific transcript variants of pain associated genes that are targeted by Rbfox1 in the primary nociceptors. We will combine Drosophila genetics with mammalian in vivo models to optimise the discovery. Based on pilot data, we predict that the extranuclear function of Rbfox1 is critical for suppression of oversensitivity to heat. Therefore, we will concentrate on the pain-related targets that are predicted to be regulated by the cytoplasmic version of Rbfox1. This will enable us to discriminate between potentially adverse and pain-associated molecules that drive oversensitivity and those that drive normal function of primary nociceptors. In doing so we will contribute compelling evidence for the importance of Rbfox1 in mediation of peripheral sensitisation and pave an avenue for targeted therapeutic strategies. In flies we have molecular reporters that measure the activity of cytoplasmic Rbfox1. By identifying the cytoplasmic Rbfox1 as critical mediator of hyperactivity in peripheral nociceptors will in short term provide justification for exploitation of this reporters as a high through-put capable readout in OA. In long-term we aim to attract industrial partners to develop new assays that are based on detection of the here identified variants of Rbfox1 targets. Through offering a simpler in vivo model we will strengthen and accelerate the drug discovery processes. Rbfox1 regulation is a homeostatic pathway which may be involved in a range of associated disorders, such as muscular dystrophy, and may benefit other pain associated conditions with non-genetic disease aetiology beyond OA.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL;NEUROLOGICAL