(6ac) Protein-Protein Interactions in Disease and Therapy

Protein-protein interactions mediate a wide range of biological processes including receptor-ligand binding, protein signaling cascades, antibody binding, cell adhesion and metabolic regulation. Dysfunction of protein-protein interactions can lead to a variety of diseases including cancers and neurodegenerative diseases. Antibody therapeutics also make use of highly specific protein interactions to provide targeted intervention. The ability to generate, characterize and evolve protein interactions provides a basis to understand disease pathogenesis and to develop potential therapies.

I am interested in how the arrangement of different amino acids leads to highly specific interactions between two proteins and to the overall disease state of an organism. In my work with David Colby at the University of Delaware we have investigated prion pathogenesis and therapy using high throughput technologies such as fluorescence activated cells sorting and deep sequencing and at multiple scales from recombinant DNA techniques to animal models. Prion diseases are a group of rapidly progressing, lethal neurodegenerative diseases that are propagated by the conversion of the native form of the prion protein (PrP^C) to an alternatively folded, disease causing form (PrP^Sc) catalyzed by the interaction of PrP^Sc with PrP^C. We used mutagenesis and directed evolution approaches to generate high affinity antibodies to disrupt prion pathogenesis and to characterize prion protein self-interactions. Future applications of the methodologies developed include investigation of allosteric enzyme sites and antibody interactions with non-antigen targets relevant to the biopharmaceutical industry. I am also interested in engineering education and have pursued several opportunities to lead students in classroom and laboratory settings.