Project R-15364

Thermal-probing microdevices to unravel phase separating condensates involved in neurodegeneration (Research)

Cells organize many, if not all of their biochemical activities in time and space within dynamic and reversible liquid-liquid phase-separated condensates of proteins and nucleic acids. Malfunctioning condensates are often implicated indiseases such as cancer and neurodegenerative disorders. Despite their therapeutic relevance, however, ourunderstanding of the structural landscapes within these complex environments, and their role in forming pathologicalaggregates, remains limited. One critical problem is the lack of comprehensive methodologies to study the structuraldynamics of the biomolecules within these complex environments, while exactly this information is key to rational drugdevelopment. In my project, I will bridge this critical technological gap by merging microfabrication engineering withreal-time fluorescence-based dynamic structural biology. With this novel methodology, I will investigate the molecularprocesses underlying disease-related structural changes of intrinsically disordered proteins (IDPs), the mainconstituents of biological condensates. The unique opportunity I offer to monitor the real-time structural dynamics ofIDPs with precise temperature control allows me to manipulate and explore the conformational landscapes of theseunstructured proteins. Ultimately, this research holds promise for developing therapeutic strategies againstneurodegenerative disorders, specifically focused on short-lived yet critical structural protein intermediates.

01 November 2024 - 31 October 2028