Principal Investigator Matthew Shoulders
A major obstacle in our field is the paucity of small molecule-regulated techniques to achieve precise, researcher control of cellular proteostasis. To address this need, we have developed two strategies. In the first approach, we regulate the regulators in each subcellular compartment. For example, we developed a highly selective and potent small molecule-regulated genetic inhibitor of the transcription factor HSF1, which is the master regulator of cytosolic proteostasis. This method is opening doors to study how global modulation of cytosolic proteostasis network composition impacts a variety of protein folding issues, including protein aggregation in neurodegenerative disease.
In a second approach, we built on state-of-the-art Cas9-based genome engineering strategies to define the levels of any desired endogenous gene transcript across a wide dynamic range using small molecules (with Prof. Amit Choudhary’s group at Harvard Medical School). The resulting chemical control of Cas9 transcriptional activity enables selective perturbation of the levels of any one or more proteostasis network components, and is key to success in our other projects.