PIF2025 - Explorando nuevas repeticiones en tándem expandidas en trastornos neuropsiquiátricos - (PID2024-161447NA-I00)

In this proposal, I hypothesize that at risk polymorphisms and/or longer tandem expansions physiologically alter neuronal function, by modulating expression or splicing of the CACNA1C gene. Thus, the main objective of this research programme is double; firstly, to determine the physiological and functional consequence of tandem repeat expansion and the underlying genetic mechanisms in post-mitotic neurons; and secondly to design strategies that successfully target these repeat expansions using Antisense Oligos (ASOs). To achieve this main objective, I will leverage a unique cellular model that allows for the differentiation of iPS cells (iPSCs) into post-mitotic neurons, combined with advanced long-read sequencing technologies, molecular biology, and genetic assays, to directly assess the impact of repeat expansions in specific genomic loci. Additionally, this proposal aims to optimize the development of antisense oligonucleotides to counteract repeat expansions.