Translating a frequent human nicotinic polymorphism – NICO-SNP

We will study the role of a frequent human coding polymorphism in a nicotinic acetyl-choline receptor (nAChR) gene, developing and using pre-clinical models and implementing a novel pharmacological approach to target specifically the mutated nAChRs. Our project is based on robust Genome-wide Association Studies (GWAS), confirmed by meta-analysis, that link a coding Single Nucleotide Polymor-phisms (SNPs) to several major diseases. Other than a robust link with smoking, they are implicated in schizophrenia (SZ), with higher statistical power than some of the standard drug targets like dopamine receptors, plus addiction to cocaine, opioids, alcohol, cannabis, and also chronic obstructive pulmonary disease (COPD), lung cancer, longevity and body-mass index. They thus present a major target for pharmacological intervention, being prominent in the population, with an average allele frequency of 28%.
Our model systems include transgenic mice and transgenic rats expressing a frequent coding polymorphism in the CHRNA5 gene, expressed in many cell types in the human brain (https: //human.brain-map.org/), rs16969968. We will study these mice by dynamic three-photon imaging, and analyse in depth the behaviour of transgenic rats using advanced Touchscreen testing.
We will provide a basis on how these "humanised" studies can be extended using novel pharmacological approaches, and the translation into the targeting of novel pathways for normalisation of altered cholinergic signaling in mental disease. The results of the proposed work will contribute to further our understanding of the underlying synaptic alterations, and will pave the way to create novel medication, acting on the genetically altered receptors, to progress towards personalised treatments for the carriers of the SNPs. We will adapt to the in vivo studies and use a novel series of positive (PAM) and negative (NAM) allosteric modulators that specifically target the a5 subunit.