Descrizione del progetto
La ricerca del controllo dello splicing alternativo
Lo splicing alternativo è un importante processo che consente la produzione di diversi RNA messaggeri e proteine da un singolo gene negli organismi complessi, compreso l’uomo. Le alterazioni dello splicing alternativo contribuiscono a malattie come il cancro e la neurodegenerazione. Sebbene i farmaci mirati abbiano recentemente fornito la prima terapia per una comune malattia genetica, resta ancora molto da imparare sui meccanismi che controllano lo splicing e sulla loro modulazione da parte di piccole molecole. Il progetto multidisciplinare UNLEASH, finanziato dal Consiglio europeo della ricerca, mira a capire come viene regolata la selezione del sito di giunzione e se può essere modulata in modo specifico da piccole molecole. Il progetto produrrà molti nuovi composti-strumento per studiare la funzione dei geni e potenzialmente contribuire allo sviluppo di nuove terapie.
Obiettivo
Alternative splicing (AS) of mRNA precursors plays important roles in tissue-specific gene regulation and biological regulatory mechanisms, as it can radically alter protein expression, cell phenotypes and physiological responses. Altered splicing also contributes to disease mechanisms, ranging from neurodegeneration to cancer. Drugs modulating AS have recently provided the first therapy for Spinal Muscular Atrophy, a common genetic disorder, illustrating the huge potential for treating many other diseases of unmet need, if only we understood the mechanisms controlling splice site selection and how to regulate them with small molecules. Unfortunately, despite decades of research, a comprehensive understanding of the mechanisms that control specificity of AS is lacking. This gap in basic knowledge prevents opportunities to harness splicing modulators as tools to study gene function, novel therapeutics or other biotech applications. This Project addresses head-on the major technical challenges that have limited progress in the AS field. Building on extensive preliminary data, we will use a multidisciplinary approach that combines chemical, structural, cellular, systems biology and machine learning to characterize mechanisms of splice site selection and identify targets for modulating these mechanisms using tool compounds. The outcomes will define key regulatory sequences, splicing factors and molecular interactions involved, thereby illuminating how the splicing machinery efficiently accommodates, yet also discriminates between, a wide range of splice site sequences. This will enable future applications harnessing splice site selection. Our primary goal is to answer the central question, ‘Is it generally possible to modulate splicing with high specificity using small molecules?’ Success will transform our basic understanding of human gene expression and unleash major opportunities for Pharma to develop new therapeutics.
Campo scientifico
Parole chiave
Programma(i)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Argomento(i)
Meccanismo di finanziamento
ERC-SYG - ERC-SYGIstituzione ospitante
08003 Barcelona
Spagna