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SynTra

Financiado

Cerrado

Controlling Gene Expression with Synthetic Cell-Penetrating Transcription Factor...

Controlling Gene Expression with Synthetic Cell-Penetrating Transcription Factors The overarching goal of SynTra is the engineering of synthetic transcription factors (STFs) that can enter cells and activate or deactivate specific genes. Traditional drugs target only a small fraction of the human proteome, whil... ver más

31/05/2027

ULEI

2M€

Presupuesto del proyecto: 2M€

Líder del proyecto

UNIVERSITEIT LEIDEN No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Fecha límite participación Sin fecha límite de participación.

Financiación concedida El organismo HORIZON EUROPE notifico la concesión del proyecto el día 2022-06-01

ERC-2021-STG: ERC STARTING GRANTS Scope:Objectives

I+D

Cerrada hace 3 años

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Duración del proyecto: 59 meses Fecha Inicio: 2022-06-01
Fecha Fin: 2027-05-31

Líder del proyecto

UNIVERSITEIT LEIDEN No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Presupuesto del proyecto 2M€

Fecha límite de participación Sin fecha límite de participación.

Descripción del proyecto The overarching goal of SynTra is the engineering of synthetic transcription factors (STFs) that can enter cells and activate or deactivate specific genes. Traditional drugs target only a small fraction of the human proteome, while compounds that can be programmed to target specific genes could address many relevant disease mechanisms, right at their basis. In aim 1, I will engineer STFs that can (1) bind to any given DNA base pair triplet and (2) enter cells. To achieve these goals, I will develop design rules for preparing minimized ?-helical scaffolds derived from zinc finger protein domains. Via peptide stapling, I will stabilize the structure of these STFs and boost their cell internalization. I will use a high throughput combinatorial screening methodology developed by me to optimize the STFs? properties. In aim 2, I will prepare multimeric STFs (consisting of multiple monomeric STFs from aim 1) that can target unique genes within the entire human genome with high specificity. I will obtain them with a combination of solid-phase and bioconjugation strategies. With a hexameric STF (recognizing 18 DNA base pairs), I will target a specific gene promoter and trigger ?-globin production as a promising strategy for sickle cell disease treatment. In aim 3, I will use STFs to disrupt cancer-related liquid-liquid phase-separated transcriptional condensates. Transcriptional condensates rely on a network between transcription factors, DNA, and coactivators, and they play a crucial role in gene transcription. With STFs, I will displace the oncogenic transcription factor MYC from its DNA binding site. I expect this interference to lead to a condensate disruption and to downregulation of oncogenic MYC-dependent transcription. SynTra will deliver powerful and practical synthetic tools for studying and targeting disease mechanisms. Researchers at the interface of biology and chemistry will use the STFs developed in SynTra, for basic research and drug development.

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