A central focus of our research is to understand the principles of protein folding and to comprehend the basis for misfolding and/or aggregation diseases such that we can develop novel therapeutic strategies using chemistry, biophysical and biological approaches.

A multidisciplinary approach to understanding degenerative diseases linked to protein aggregation is a main focus of our laboratory. We concentrate on Alzheimer's disease, as well as the transthyretin- and light-chain-based amyloid diseases. Mechanistic studies of protein aggregation have led to small molecule and macromolecular amyloid fibril inhibition strategies, including the drug, tafamidis, discovered by the Kelly lab and sold by Pfizer. Our efforts to seek an aggregate structure-proteotoxicity relationship have led to insight into the etiology of these pathologies. Chemical synthesis of small molecule inhibitors designed to manipulate protein energetics is a significant component of our research program. We also use cell-based screens to discover mediators of the protein homeostasis network, including stress-responsive signaling pathway activators (in collaboration with the Wiseman lab) and autophagy activators, which should be generally useful to ameliorate amyloid diseases.