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In an interdisciplinary project supported by a Sinergia grant of the Swiss National Science Foundation, we investigate the molecular underpinnings of gene regulation in muscle plasticity at the atomic level. At the center of this regulation lies PGC-1α, a transcriptional co-activator and master regulator of metabolic processes. PGC-1α dysfunction has been linked to obesity, diabetes, muscular dystrophies, neurodegenerative diseases, and cancer. Despite its importance, the molecular mechanisms by which PGC-1α-a large, predominantly disordered protein with only a single structured RRM domain-senses cellular metabolic states and translates this information into transcriptional activation remain elusive.
This postdoctoral project aims to unravel the molecular mechanisms of PGC-1α function by combining advanced biophysical methods, with a particular emphasis on NMR spectroscopy for structural and dynamic insights into intrinsically disordered proteins, as well as complementary biophysical approaches to characterize protein function and interaction. By applying these techniques, we seek to uncover how PGC-1α integrates signals to regulate transcription, providing fundamental insights into metabolism and disease. The work is a close collaboration with the group of Prof. Christoph Handschin, complementing our structural research with genetic elucidation of structure-function aspects, spanning from molecular biology to animal physiology.