Project description
Coordinating protein synthesis and folding in metazoans
To function, proteins fold into complex 3D shapes. Since proteins often begin to fold during messenger ribonucleic acid (mRNA) translation, codon choice and transfer ribonucleic acid (tRNA) supply can further this process by modulating translation speed. Scientists don’t know how metazoans exploit this mechanism to ensure protein homeostasis. The EU-funded TransTempoFold project will establish how tRNA pools and the regulatory networks for protein biogenesis and homeostasis are tailored to specialised proteomes in different cell types. It will focus on stem cells and differentiated progeny lines and develop a method to modulate cellular tRNA pools in vivo. The project will define how diverse metazoan cell proteomes are established and maintained and reveal why some cells tolerate misfolded proteins better than others.
Objective
Proteins function only after folding into complex three-dimensional shapes. Loss of protein conformation is detrimental for cellular health, and a hallmark of aging and diverse human diseases. To ensure proteome integrity, cells rely on an intricate interplay between protein synthesis, folding, and quality control. Since proteins often begin to fold during mRNA translation, codon choice and tRNA supply can promote this process by modulating translation speed. How metazoans exploit this mechanism to ensure protein homeostasis over a wide range of cells and tissues, or why some cell types are more vulnerable to translation defects and proteome damage remains unknown. Here, I will define how tRNA pools and the regulatory networks for protein biogenesis and homeostasis are tailored to specialized proteomes in different cell types. I propose a multiscale systems approach centred around: i) stem cells and differentiated progeny lines as a powerful model system, and ii) a novel method to modulate cellular tRNA pools in vivo. Isogenic lines of a range of normal cellular states will be created through the differentiation of human pluripotent stem cells into neuronal and cardiac lineages. In these lineages, I will first quantitate tRNA expression and abundance, and dissect their impact on translation dynamics with ribosome profiling. Second, I will use systematic depletion of individual tRNAs to explore how different cell types respond to imbalanced tRNA pools, and define how mRNA sequence and protein structure patterns program protein folding. Third, I will use loss-of-function screens to uncover evolutionarily conserved regulators of proteome integrity as a function of cell identity. This project will define how diverse metazoan cell proteomes are established and maintained, and reveal why some cells tolerate misfolded proteins better than others.
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: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
- natural sciences biological sciences biochemistry biomolecules proteins proteomics
- medical and health sciences basic medicine physiology homeostasis
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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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H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC)
MAIN PROGRAMME
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Topic(s)
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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.
ERC-STG - Starting Grant
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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-2018-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.
80539 MUNCHEN
Germany
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.