Investigating the GWAS-identified target NCX3 in nociception (360G-Wellcome-203802_Z_16_A)

Evolutionary, pain is a protective sensation. However, it can persist beyond its usefulness and become debilitating for patients. Chronic pain affects up to one half of the population in the UK (Fayaz et al, 2016). Currently, the treatment options are limited and discovering new drug targets is of great importance. In a recent genetic study (genome-wide association study), we identified a gene (SLC8A3 encoding the protein NCX3), which was associated with higher pain sensitivity to experimental pain stimuli in healthy participants. My thesis will therefore focus on studying the function of NCX3 on a molecular, cellular and systems level. NCX3 is an important part of the machinery that moves ions in and out of cells. Its role in pain is poorly understood, but previous reports show that it is involved in regulating Ca2+ levels in pain-sensing neurones. Inhibition of NCX3 can cause increased Ca2+ in these cells leading to higher activation of the central nervous system and increasing pain sensation. To investigate the function of NCX3, I will use genetically modified mice lacking the gene as well as isolated pain-sensing neurones. Our genetic data, combined with published results, makes NCX3 an attractive target for future research and drug discovery.