Project description
Protein-based drugs that control gene expression
Transcription factors are proteins that recognise and bind specific DNA sequences, participating in the initiation and regulation of gene expression. The EU-funded SynTra project proposes to develop synthetic transcription factors (STFs) that can bind to unique genes and alter their expression pattern. Researchers will engineer STFs that can efficiently enter cells and recognise stretches of DNA, driving gene transcription or potentially displacing other transcription factors such as MYC. Being able to switch genes on and off as desired would serve as a therapy for many diseases such as sickle cell disease or cancer.
Objective
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.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
This project's classification has been validated by the project's team.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
This project's classification has been validated by the project's team.
Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.1 - European Research Council (ERC)
MAIN PROGRAMME
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Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
HORIZON-ERC - HORIZON ERC Grants
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Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) ERC-2021-STG
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Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.
2311 EZ Leiden
Netherlands
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.