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Harnessing the splicing code for targeted control of gene expression

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.... ver más

31/05/2029

FUNDACIO PRIVADA C...

5M€

Presupuesto del proyecto: 5M€

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FUNDACIO PRIVADA CENTRE DE REGULACIO GENOMICA Otras actividades deportivas asociacion

TRL 4-5 | 50K€

Ver 3 Participantes

Financiación concedida El organismo HORIZON EUROPE notifico la concesión del proyecto el día 2023-03-02

ERC-2022-SyG: ERC Synergy Grants Objective:Objectives

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3 Participantes

FUNDACIO PRIVADA CENTRE DE R...

2.50M€ | Lider

HMGU

2.50M€ | Participante

UNIVDUN

N.D. | Participante

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Duración del proyecto: 74 meses Fecha Inicio: 2023-03-02
Fecha Fin: 2029-05-31

Líder del proyecto

FUNDACIO PRIVADA CENTRE DE REGULACIO GENOMICA Otras actividades deportivas asociacion

TRL 4-5 | 50K€

Presupuesto del proyecto 5M€

Descripción del proyecto 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.

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