Our goal is to understand how human cells maintain their proteins in a functional and balanced state. The cellular pathways safeguarding protein function and balance are termed the proteostasis network. We aim to elucidate how the proteostasis network dynamically adapts to the needs of the cell and how it is challenged and rewired in diseases, especially neurodegenerative diseases and cancer.
We use an interdisciplinary approach to address these questions. Our CRISPR/Cas9-based functional genomics technology enables us to query the function of each gene in the human genome in a process of interest. We have implemented this platform in human iPSCs and derived cell types, including neurons, astrocytes, and microglia, which enables us to dissect the mechanisms of neurodegenerative diseases in the relevant human cell types. We systematically investigate interactions between genes to identify pathways and networks. The resulting genetic interaction maps can reveal how the proteostasis network is rewired in disease contexts. We use biochemistry, biophysics and cell biology to uncover the mechanisms by which genes function in normal and disease states of the cell.