Dissecting mechanisms of intracellular cholesterol transport using chemical genetic tools

ongoing

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.