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.
Before proteome repair can mature as a therapeutic strategy, we must learn much more about how proteins fold in the cell and about the specific cellular mechanisms we can exploit to rescue pathologic protein folding problems without globally disrupting cell health. Few selective chemical and chemical biologic tools currently exist to explore these issues in vivo. The Shoulders Laboratory is focused on integrating the tools of chemistry and biology to elucidate the complex pathways responsible for maintaining cellular protein homeostasis. Our lab employs a multi-disciplinary approach to (1) understand at the molecular level how the cell remodels itself to address challenges to protein homeostasis, (2) elucidate the pathophysiology of protein folding-related diseases with poorly defined etiologies, and (3) target the biological processes we uncover for the development of new small molecule probes, tools, and (ultimately) drugs.