Structural elucidation of human membrane and cytosolic proteins involved in endo- and epithelial cell:cell adhesion and intercellular transport.
We hypothesize proteins at tight junctions possess unique overall folds and local conformations that confer perm selectivity to epithelia. The goal of this Project is to elucidate 3D structures of individual human membrane and cytosolic proteins,and their associated protein complexes. Structural investigation of tight junction proteins will clarify their roles in endo-and epithelial cell adhesion and paracellular transport.
Biochemical and biophysical characterization of protein:protein interactions essential for macromolecular assemblies.
For tight junctions to govern paracellular transport their proteins must interact in novel ways within the same membrane plane, and across intercellular space between neighboring cells. The aim of this Project is to biochemically and biophysically characterize protein:protein interactions essential for tight junction macromolecular assemblies. This work will progress understanding of functionally-relevant protein interactions used by tight junctions, elucidating the molecular bases that control epithelial permeability and maintain tissue homeostasis.
Development of biomolecular probes for investigating structure—function relationships between multi-protein complexes.
Disruptions to formation of tight junctions are hallmark to diseases and a potential path for therapeutic development aimed at modulating tight junction permeability, like at the blood-brain barrier. Molecules of various size employ abundant means to disrupt tight junctions, resulting in unique effects and specific disorders. The goal of the Project is to develop biomolecular probes for investigating tight junction structure—function. The research will reveal the molecular bases disease-causing agents use to render epithelia vulnerable to permeation by disruption of tight junction ultrastructure, and discover new potentially therapeutic molecules.