Project description
Insight into protein-misfolding diseases
There are more than 70 diseases caused by proteins that fail to fold correctly, leading to disrupted cellular function. Around one third of these diseases are caused by misfolding-prone membrane proteins (MisMPs). However, MisMPs remain largely understudied due to technical challenges, limiting their therapeutic value. The EU-funded ProMisMe project aims to overcome this by engineering bacteria and yeast as platforms to produce and screen vast libraries of drug-like molecules for their ability to rescue MisMP misfolding. Promising compounds will be validated in biochemical, biophysical and mammalian cell assays. This platform could serve as a drug discovery framework for the identification of new therapeutic candidates against protein-misfolding diseases.
Objective
Protein misfolding diseases (PMDs) are a large group of human disorders caused by the misfolding of specific proteins. They include conditions with high socio-economic impact, such as Alzheimer’s disease, cystic fibrosis, obesity and type 2 diabetes, and the majority of them remain incurable. Among the >70 PMDs, about 1/3 are caused by misfolding-prone membrane proteins (MisMPs). Despite their significance, and mainly due to the difficulties associated with MisMP overexpression, isolation and characterization, the PMD scientific community has largely overlooked MisMP-associated PMDs, thus limiting opportunities for drug discovery. In ProMisMe, we will develop engineered bacteria and yeast, which can function as broadly applicable discovery platforms for compounds that rescue MisMP misfolding. These compounds will be selected from libraries of drug-like molecules biosynthesized in these microbes using a technology that allows the facile production of tens of millions to tens of billions of different test molecules. These libraries will then be screened in the same microbial cells that produce them and the rare molecules that rescue MisMP misfolding effectively will be selected by ultrahigh-throughput screening. The effect of the selected molecules on MisMP folding will then evaluated by biochemical and biophysical methods, while their ability to reverse MisMP-induced pathogenicity will be tested in appropriate mammalian cell assays. The molecules that rescue the misfolding and associated pathogenicity of the target MisMPs will become therapeutic candidates against the corresponding diseases. This procedure will be applied for different MisMPs to identify potential therapeutics for two serious PMDs: Usher Syndrome III and Charcot-Marie-Tooth disease. Successful realization of ProMisMe will provide invaluable therapeutic leads against major diseases and a more widely applicable framework for drug discovery against diseases caused by membrane protein misfolding.
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.
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.
- natural sciences biological sciences microbiology bacteriology
- natural sciences biological sciences biochemistry biomolecules proteins
- medical and health sciences clinical medicine endocrinology diabetes
- medical and health sciences health sciences nutrition obesity
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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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HORIZON.4.1 - Widening participation and spreading excellence
MAIN PROGRAMME
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HORIZON.4.1.5 - Fostering brain circulation of researchers and excellence initiatives
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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-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships
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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) HORIZON-WIDERA-2022-TALENTS-04
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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.
166 72 VARI-ATHENS
Greece
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.