Description du projet
Contrôler l’épissage alternatif
L’épissage alternatif (EA) est un processus important qui permet la production de différents ARN messagers et protéines à partir d’un seul gène dans les organismes complexes, y compris chez l’homme. Les altérations de l’EA contribuent à des maladies telles que le cancer et la neurodégénérescence. Si les médicaments ciblant l’épissage ont récemment fourni la première thérapie pour une maladie génétique courante, il reste encore beaucoup à apprendre sur les mécanismes contrôlant ce processus et leur modulation grâce aux petites molécules. Financé par le Conseil européen de la recherche, le projet multidisciplinaire UNLEASH vise à comprendre comment la sélection des sites d’épissage est régulée et si elle peut être spécifiquement modulée par de petites molécules. Le projet permettra de créer de nombreux composés outils innovants pour étudier la fonction des gènes et, éventuellement, contribuer à la mise au point de nouvelles thérapies.
Objectif
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.
Champ scientifique
Mots‑clés
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Thème(s)
Régime de financement
ERC-SYG - ERC-SYGInstitution d’accueil
08003 Barcelona
Espagne