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Dissecting mechanisms of intracellular cholesterol transport using chemical genetic tools

Project description

Uncovering the process of cholesterol transport

Cholesterol is a vital lipid that maintains membrane integrity and is implicated in cell signalling and proliferation. Its distribution inside cells is tightly controlled, but many aspects of intracellular cholesterol transport remain poorly understood. This is due to overlapping functions among transport proteins and the lack of effective molecular probes. With the support of the Marie Skłodowska-Curie Actions programme, the CHOTENICS project aims to uncover the mechanisms of cholesterol transport through fast-acting small molecules that modulate cholesterol distribution. The proposed novel chemical genetics approach is expected to reveal new biological pathways and drug targets, offering therapeutic insights into the process of cholesterol transport.

Objective

Cholesterol is a unique lipid, essential for membrane integrity, cell signalling and cell proliferation. Accordingly, mammalian organisms have evolved an elaborate myriad of mechanisms to control cholesterol transport and distribution within cells. However, our understanding of these mechanisms remains incomplete due to (i) the functional redundancy inherent among cholesterol transporters, which limits their study through conventional genetic approaches, and (ii) the general lack of suitable probes.
CHOTENICS aims to address this knowledge gap by exploring intracellular cholesterol transport using a novel chemical genetics approach. The project is built on the hypothesis that fast-acting chemical tools can rapidly modulate subcellular cholesterol distribution, enabling direct dissection of transport mechanisms before indirect effects manifest. To accomplish this goal, a high-content screening assay will be first developed to track cholesterol localisation, and then used to identify small molecules that modulate its transport. Chemical optimisation and mass spectrometry-based target identification will provide target hypotheses that will be further tested using biophysical assays and validated via genetic methods. This integrated approach is ground-breaking since it will reveal cholesterol transport pathways, mechanisms, and drug targets, and will uncover the therapeutic potential of targeting cholesterol transport processes.
CHOTENICS is designed to complement the current knowledge of the researcher in chemical synthesis and biological assay development, provide specific training in proteomics and genetics, and equip the researcher with new technical and transferable skills to become a well-rounded chemical biologist. The host organisation will gain from the researcher’s expertise in chemistry and biology and find opportunities to expand its network of international collaborations.

Fields of science (EuroSciVoc)

Keywords

Programme(s)

Topic(s)

Funding Scheme

HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships

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Call for proposal

(opens in new window) HORIZON-MSCA-2024-PF-01

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Coordinator

DANMARKS TEKNISKE UNIVERSITET
Net EU contribution
€ 247 553,28
Address
ANKER ENGELUNDS VEJ 101
2800 Kongens Lyngby
Denmark
Region
Danmark Hovedstaden Københavns omegn
Activity type
Higher or Secondary Education Establishments
Links
Total cost
No data