Maintaining the proper three-dimensional structure, concentration, activity, and localization of proteins is a critical and constant challenge for all organisms. Dysregulated protein homeostasis is inextricably linked to disease states. Accordingly, the most prominent diseases of modern times—including neurodegenerative diseases like Alzheimer’s disease, diabetes, loss-of-function diseases like cystic fibrosis, many types of cancer, and even viral infections—are either caused directly by a failure to maintain protein homeostasis or reliant on innate cellular protein folding mechanisms. Proteome repair achieved by targeting the cellular mechanisms that regulate protein folding could transform the therapeutic options for broad swaths of protein folding-related disease. Critically, methods to intervene in a single important protein folding pathway could be applied to multiple, diverse pathologies.
The Shoulders laboratory is developing and applying a chemical biology and small molecule-derived toolbox to probe the cell's protein folding network and manipulate it in defined ways. We employ a multi-disciplinary approach to understand how the cell remodels itself to address challenges to protein homeostasis, to elucidate the pathophysiology of protein folding-related diseases with poorly defined etiologies, and to target the biological processes we uncover for the development of first-in-class small molecule drugs.