Project description
Sterol-based affinity probes for CTP inhibitor’s identification
Cholesterol is essential for cell membranes, regulating fluidity and signalling. Intracellular cholesterol transport proteins (CTPs) maintain cholesterol levels, but their dysfunction is linked to diseases such as cardiovascular issues and Alzheimer’s. Currently, there are no probes available to study CTP inhibitors, and only a few inhibitors have been identified, limiting our understanding of their selectivity and therapeutic potential. Supported by the Marie Skłodowska-Curie Actions programme, the CholMap project will develop a universal sterol-based affinity probe that binds all CTPs and evaluates the selectivity of CTP inhibitors in cells. The findings will help identify new sterol-binding proteins and potential drug targets, while also providing a valuable dataset for the research community.
Objective
Cholesterol is a structural component of membranes and plays a key role in human health by regulating the fluidity of membranes and affecting signaling pathways. Intracellular cholesterol transport proteins (CTP) are responsible for maintaining cholesterol homeostasis by regulating local cholesterol concentrations, arising from de novo biosynthesis or dietary sources. Dysregulated cholesterol transport is associated with cardiovascular disease but also Alzheimer's and cancer. Despite the obvious importance of CTPs, a chemical probe to investigate binding, inhibition and selectivity profiling of CTP inhibitors does not exist. CTPs are all structurally related in their cholesterol binding site. Therefore, the development of a selective modulator to study their individual function and possible therapeutic relevance is challenging. Only a few CTP inhibitors have been reported so far and it has not been possible to conclusively evaluate their cellular selectivity. In CholMap, I aim to introduce a universal sterol-based affinity probe with the ability to bind all CTPs and evaluate the selectivity of CTP inhibitors in cells. This sterol-based probe would be bifunctional containing a diazirine, which is transformed into a carbene via UV irradiation for covalent binding to CTPs, and an alkyne for binding to a functional tag via click chemistry. I will synthesize differently constituted probes and test them in vitro for their efficiency. An optimized sterol-based affinity probe would be used in a chemoproteomic workflow to determine the target engagement and the selectivity of different CTP inhibitors. The introduction of a universal sterol-based affinity probe in combination with a chemoproteomic workflow would constitute the first example of CTP selectivity profiling in cells. The results will also enable me to uncover new sterol-binding proteins including new potential drug targets, as well as providing a large dataset accessible to the whole research field.
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.
- medical and health sciences basic medicine neurology neurodegenerative diseases dementia alzheimer
- natural sciences biological sciences biochemistry biomolecules proteins
- medical and health sciences clinical medicine oncology
- 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)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA)
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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.
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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
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(opens in new window) HORIZON-MSCA-2024-PF-01
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2800 Kongens Lyngby
Denmark
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